Benzodioxole derivatives

ABSTRACT

The present invention relates to compounds of the general formula 
                         
and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases such as obesity by selective modulation of CB1 receptors.

PRIORITY TO RELATED APPLICATIONS

This application is a Division of Ser. No. 10/626,681, filed Jul. 24,2003, which is now pending.

BACKGROUND OF THE INVENTION

The present invention relates to the use of antagonists of the CB₁cannabinnoid receptor. Two different subtypes of cannabinoid receptors(CB₁ and CB₂) have been isolated and both belong to G protein coupledreceptor superfamily. An alternative spliced form of CB₁, CB_(1A), hasalso been described, but it did not exhibit different properties interms of ligand binding and receptor activation than CB₁ (D.Shire, C.Carrillon, M. Kaghad, B. Calandra, M. Rinaldi-Carmona, G. Le Fur, D.Caput, P. Ferrara, J. Biol. Chem. 270 (8) (1995) 3726-31). The CB₁receptor is mainly located in the brain, whereas the CB₂ receptor ispredominately distributed in the periphery primarily localized in spleenand cells of the immune system (S. Munro, K. L. Thomas, M. Abu-Shaar,Nature 365 (1993) 61-61).

Therefore in order to avoid side effects a CB₁-selective compound isdesirable. Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is the principalpsychoactive compound in the Indian hemp (Y. Gaoni, R. Mechoulam, J. Am.Chem. Soc., 86 (1964) 1646), canabis savita (marijuana), which is usedin medicine since ages (R. Mechoulam (Ed.) in “Cannabinoids astherapeutic Agents”, 1986, pp. 1-20, CRC Press). Δ⁹-THC is anon-selective CB₁/₂ receptor agonist and is available in the USA asdronabinol (marinol®) for the alleviation of cancer chemotherapy-inducedemesis (CIE) and the reversal of body weight loss experienced by AIDSpatients through appetite stimulation. In the UK Nabolinone (LY-109514,Cesamet®), a synthetic analogue of □⁹-THC, is used for CIE (R. G.Pertwee, Pharmaceut. Sci. 3 (11) (1997) 539-545, E. M. Williamson, F. J.Evans, Drugs 60 (6) (2000) 1303-1314).

Anandamide (arachidonylethanolamide) was identified as the endogenousligand (agonist) for CB₁ (R. G. Pertwee, Curr. Med. Chem., 6 (8) (1999)635-664;W. A. Devane, L. Hanus, A. Breuer, R. G. Pertwee, L. A.Stevenson, G. Griffin, D. Gibson, A. Mandelbaum, A. Etinger, R.Mechoulam, Science 258 (1992) 1946-9). Anandamide and2-arachidonoylglycerol (2-AG) modulate at the presynaptic nerve teminalnegatively adenylate cyclase and voltage-sensitive Ca²⁺ channels andactivates the inwardly rectifying K⁺ channel (V. Di Marzo, D. Melck, T.Bisogno, L. De Petrocellis, Trends in Neuroscience 21 (12) (1998)521-8), thereby affecting neurotransmitter release and/or action, whichdecreases the release of neurotransmitter (A. C. Porter, C. C. Felder,Pharmacol. Ther., 90 (1) (2001) 45-60).

Anandamide as Δ⁹-THC also increases feeding through CB₁receptor-mediated mechanism. CB₁ selective antagonists block theincrease in feeding associated with administration of anandamide (C. M.Williams, T. C. Kirkham, Psychopharmacology 143 (3) (1999) 315-317; C.C. Felder, E. M. Briley, J. Axelrod, J. T. Simpson, K. Mackie, W. A.Devane, Proc. Natl. Acad. Sci. U. S. A. 90 (16) (1993) 7656-60) andcaused appetite suppression and weight loss (G. Colombo, R. Agabio, G.Diaz, C. Lobina, R. Reali, G. L. Gessa, Life Sci. 63 (8) (1998)L113-PL117).

Leptin is the primary signal through which the hypothalamus sensesnutritional state and modulates food intake and energy balance.Following temporary food restriction, CB1 receptor knockout mice eatless than their wild-type littermates, and the CB1 antagonist SR141716Areduces food intake in wild-type but not knockout mice. Furthermore,defective leptin signaling is associated with elevated hypothalamic, butnot cerebellar, levels of endocannabinoids in obese db/db and ob/ob miceand Zucker rats. Acute leptin treatment of normal rats and ob/ob micereduces anandamide and 2-arachidonoyl glycerol in the hypothalamus.These findings indicate that endocannabinoids in the hypothalamus maytonically activate CB1 receptors to maintain food intake and form partof the neural circuitry regulated by leptin (V. Di Marzo, S. K.Goparaju, L. Wang, J. Liu, S. Bitkai, Z. Jarai, F. Fezza, G. I. Miura,R. D. Palmiter, T. Sugiura, G. Kunos, Nature 410 (6830) 822-825).

SR-141716A, a CB1 selective antagonist/inverse agonist is currentlyundergoing phase III clinical trials for the treatment of obesity. In adouble blind placebo-controlled study, at the doses of 5, 10 and 20 mgdaily, SR 141716 significantly reduced body weight when compared toplacebo (F. Barth, M. Rinaldi-Carmona, M. Arnone, H. Heshmati, G. LeFur, “Cannabinoid antagonists: From research tools to potential newdrugs.” Abstracts of Papers, 222nd ACS National Meeting, Chicago, Ill.,United States, Aug. 26-30, 2001).

Other compounds which have been proposed as CB1 receptor antagonists areaminoalkylindols (AAI; M. Pacheco, S. R. Childers, R. Arnold, F.Casiano, S. J. Ward, J. Pharmacol. Exp. Ther. 257 (1) (1991) 170-183),like 6-bromo-(WIN54661; F. M. Casiano, R. Arnold, D. Haycock, J. Kuster,S. J. Ward, NIDA Res. Monogr. 105 (1991) 295-6) or 6-iodopravadoline(AM630, K. Hosohata, R. M. Quock, R. M; Hosohata, T. H. Burkey, A.Makriyannis, P. Consroe, W. R. Roeske, H. I. Yamamura, Life Sci. 61(1997) 115-118; R. Pertwee, G. Griffin, S. Fernando, X. Li, A. Hill, A.Makriyannis, Life Sci. 56 (23-24) (1995) 1949-55). Arylbenzo[b]thiophene and benzo[b]ffuran (LY320135, C. C. Felder, K. E. Joyce, E. M.Briley, M. Glass, K. P. Mackie, K. J. Fahey, G. J. Cullinan, D. C.Hunden, D. W. Johnson, M. O. Chaney, G. A. Koppel, M. Brownstein, J.Pharmacol. Exp. Ther. 284 (1) (1998) 291-7) disclosed in WO9602248, U.S.Pat. No. 5,596,106, 3-alkyl-(5,5-diphenyl)imidazolidinediones (M.Kanyonyo, S. J. Govaerts, E. Hermans, J. H. Poupaert, D. M. Lambert,Bioorg. Med. Chem. Lett. 9 (15) (1999) 2233-2236.) as well as3-alkyl-5-arylimidazolidinediones (F. Ooms, J. Wouters, O. Oscaro. T.Happaerts, G. Bouchard, P.-A. Carrupt, B. Testa, D. M. Lambert, J. Med.Chem. 45 (9) (2002) 1748-1756) are known to antagonize the CB₁ receptorrespectively act as an inverse agonist on the hCB₁ receptor. WO0015609(FR2783246-A1), WO0164634 (FR2805817-A1), WO0228346, WO0164632(FR2805818-A1), WO0164633 (FR2805810-A1) disclosed substituted1-bis(aryl)methyl-azetidines derivatives as antagonists of CB₁. InWO0170700 4,5-dihydro-1H-pyrazole derivatives are described as CB₁antagonists. In several patents bridged andnon-bridged1,5-diphenyl-3-pyrazolecarboxamide derivatives are disclosedas CB₁ antagonists/inverse agonists (WO0132663, WO0046209, WO9719063,EP658546, EP656354, U.S. Pat. No. 5,624,941, EP576357, U.S. Pat. No.3,940,418). More recently other diverse structural classes have beendisclosed as CB receptor modulators (WO0158869, WO0224630).

SUMMARY OF THE INVENTION

The present invention is concerned with novel benzodioxole derivativesof the formula:

their manufacture, pharmaceutical compositions containing them and theiruse as medicaments. The active compounds of the present invention areselective CB₁ receptor antagonists and are useful in treating obesityand other disorders.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of formula (I):

wherein

-   R¹ and R² are independently unsubstituted phenyl, or phenyl which is    mono-, di- or tri-substituted, independently, by hydroxy, lower    alkyl, lower alkoxy, perfluoro-lower alkyl, perfluoro-lower alkoxy,    alkanoyl, cyano, nitro or halogen; or R¹ and R² together with the    carbon atom to which they are attached form a    10′,11′-dihydro-2,5′-[5H]dibenzo-[a,d]cycloheptene residue;-   R³ and R⁴ are independently hydrogen, halogen, hydroxy, lower alkyl,    lower alkoxy, perfluoro-lower alkyl, alkanoyl or cyano;-   R⁵ is hydrogen, lower alkyl, lower alkylsulfonyl, cycloalkyl lower    alkyl or hydroxy-lower alkyl;-   R⁶ is Y—R⁸, lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower    alkoxy-lower alkyl, lower alkylaminocarbonyl-lower alkyl,    heterocyclyl, cycloalkyl, phenyl or phenyl lower alkyl, wherein the    phenyl moiety may optionally be mono-, di- or tri-substituted,    independently, by lower alkyl, lower alkoxy, halogen,    perfluoro-lower alkyl, hydroxy, alkanoyl or cyano; or-   R⁶ is hydrogen when X is —C(O)— or —SO₂—; or-   R⁵ and R⁶ together with the nitrogen atom to which they are attached    form a 4-, 5-, 6- or 7-membered monocyclic or a 8-, 9-, 10-, or    12-membered bicyclic, saturated or unsaturated heterocyclic ring    which may optionally contain one or two further heteroatoms    independently selected from O, N and S, said heterocyclic ring being    optionally mono-, di- or tri-substituted, independently, by lower    alkyl, lower alkoxycarbonyl, hydroxy lower alkyl, lower alkoxy-lower    alkyl, di-lower alkylcarbamoyl, carbamoyl, lower alkylcarbonyl    amino, oxo, dioxo, alkanoyl, amino lower alkyl, hydroxy, lower    alkoxy, halogen, perfluoro-lower alkyl, cyano, heteroaryl, or by    phenyl or phenyl lower alkyl, wherein the phenyl moiety may    optionally be mono-, di- or tri-substituted, independently, by lower    alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy,    alkanoyl or cyano;-   R⁷ is hydrogen, halogen, lower alkyl or cyano;-   R⁸ is phenyl, cycloalkyl, heterocyclyl or heteroaryl;-   X is a single bond, —CH₂—, —C(O)—, —SO₂— or —SO₂NH—;-   Y is —CH₂—, —C(O)—, —NH— or —SO₂—;    and pharmaceutically acceptable salts thereof.

Unless otherwise indicated, the following definitions are set forth todefine the meaning and scope of the various terms used to describe theinvention herein.

In this specification the term “lower” is used to mean a groupconsisting of one to six, preferably of one to four carbon atom(s).

The term “halogen” refers to fluorine, chlorine, bromine and iodine,preferably to chlorine, fluorine and bromine, most preferably tochlorine and fluorine.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, more preferably one to ten carbon atoms.

The term “lower alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent alkyl radical of oneto six carbon atoms, preferably one to four carbon atoms. This term isfurther exemplified by radicals such as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, 3-methylbutyl,n-hexyl, 2-ethylbutyl and the like.

The term “cycloalkyl” refers to a monovalent carbocyclic radical ofthree to six, preferably three to five carbon atoms. This term isfurther exemplified by radicals such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

The term “lower alkylsulfonyl” refers to the group R′—SO₂—, wherein R′is lower alkyl.

The term “lower alkylcarbonyl” refers to the group R′—CO—, wherein R′ islower alkyl.

The term “alkoxy” refers to the group R′—O—, wherein R′ is alkyl. Theterm “lower-alkoxy” refers to the group R′—O—, wherein R′ islower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy, with methoxy beingespecially preferred.

The term “lower alkoxycarbonyl” refers to the group R′—O—C(O)—, whereinR′ is lower alkyl.

The term “perfluoro-lower alkyl” refers to a lower alkyl group whereinall of the hydrogens of the lower alkyl group are substituted orreplaced by fluoro. Among the preferred perfluoro-lower alkyl groups aretrifluoromethyl, pentafluoroethyl and heptafluoropropyl, withtrifluoromethyl being especially preferred.

The term “alkanoyl” refers to a group C(O)—R wherein R is hydrogen orlower alkyl.

Examples of alkanoyl groups are formyl, acetyl, propionyl and the like.

The term “phenyl-lower alkyl” refers to a phenyl group which is attachedto the remainder of the molecule via a lower alkylene group, such asmethylene, ethylene propylene or butylene, preferably methylene andethylene. Preferable phenyl-lower alkyl residues are benzyl and1-phenylethyl.

The term “amino lower alkyl” refers to a lower alkyl radical substitutedwith an amino group.

The term “heterocyclyl” refers to a 5- or 6-membered saturatedheterocyclic residue containing one or two heteroatoms selected fromnitrogen, oxygen and sulfur. Examples of heterocyclyl residues aremorpholino, tetrahydrofuranyl, pyrrolidinyl, piperidinyl and azepanyl.

The term “heteroaryl” refers to an aromatic monovalent mono- orpoly-carbocyclic radical having at least one heteroatom selected from N,O and S. Examples of heteroaryl groups are pyridinyl, pyrazinyl andpyrimidinyl. Such heteroaryl residues may optionally be mono-, di-, ortri-substituted, independently, by lower alkoxy, lower alkyl,perfluoro-lower alkyl, cyano and alkanoyl, preferably by halogen andperfluoro-lower alkyl.

The term “pharmaceutically acceptable salts” embraces salts of thecompounds of formula (I) with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,fumaric acid, succinic acid, tartaric acid, methanesulphonic acid,salicylic acid, p-toluenesulphonic acid and the like, which are nontoxic to living organisms. Preferred salts with acids are formates,maleates, citrates, hydrochlorides, hydrobromides and methanesulfonicacid salts, with hydrochlorides being especially preferred.

In one embodiment, the present invention relates to compounds of formula(I):

wherein

-   R¹ and R² are independently unsubstituted phenyl, or phenyl which is    mono-, di- or tri-substituted, independently, by hydroxy, lower    alkyl, lower alkoxy, perfluoro-lower alkyl, alkanoyl, cyano or    halogen;-   R³ and R⁴ are independently hydrogen, halogen, hydroxy, lower alkyl,    lower alkoxy, perfluoro-lower alkyl, alkanoyl or cyano;-   R⁵ is hydrogen or lower alkyl;-   R⁶ is phenyl or phenyl lower alkyl, wherein the phenyl moiety may    optionally be mono-, di- or tri-substituted, independently, by lower    alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy,    alkanoyl or cyano; or-   R⁵ and R⁶ together with the nitrogen atom to which they are attached    form a 5-, 6- or 7-membered monocyclic or a 9- or 10-membered    bicyclic, saturated or unsaturated heterocyclic ring which may    optionally contain one or two further heteroatoms independently    selected from O, N and S, said heterocyclic ring being optionally    mono-, di- or tri-substituted, independently, by lower alkyl, lower    alkoxycarbonyl, hydroxy lower alkyl, alkanoyl, amino lower alkyl,    hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano,    heteroaryl, or by phenyl or phenyl lower alkyl, wherein the phenyl    moiety may optionally be mono-, di- or tri-substituted,    independently, by lower alkyl, lower alkoxy, halogen,    perfluoro-lower alkyl, hydroxy, alkanoyl or cyano;-   X is —CH₂—, —C(O)— or —SO₂—;    and pharmaceutically acceptable salts thereof.

In one ebodiment, R¹ and R² are unsubstituted phenyl. In anotherembodiment R¹ and R² are independently phenyl which is mono-, di- ortri-substituted, preferably mono- or di-substituted, independently, byhydroxy, lower alkyl such as methyl, lower alkoxy such as methoxy,perfluoro-lower alkyl such as trifluoromethyl, perfluoro-lower alkoxysuch as trifluoromethoxy, alkanoyl, cyano, nitro or halogen such aschlorine, fluorine and bromine.

In another embodiment R¹ and R² are independently unsubstituted phenylor phenyl which is mono-, di- or tri-substituted, preferably mono- ordi-substituted, independently, by lower alkyl such as methyl, loweralkoxy such as methoxy, perfluoro-lower alkyl such as trifluoromethyl,perfluoro-lower alkoxy such as trifluoromethoxy, cyano, nitro or halogensuch as chlorine, fluorine and bromine.

In another embodiment, the present invention relates to a compound offormula (I) as defined above, wherein R¹ and R² are independentlyphenyl, which is mono-, di- or tri-substituted, independently, byhydroxy, lower alkyl, lower alkoxy, perfluoro-lower alkyl, alkanoyl,cyano or halogen; preferable substituents of phenyl residues R¹ and R²are lower alkyl, such as methyl, lower alkoxy, such as methoxy, andhalogen, such as fluoro and chloro. Preferably R¹ and R² areindependently phenyl which is mono- or di-substituted, independently, byhalogen, preferably fluoro, chloro or bromo, more preferably fluoro orchloro, or by lower alkoxy, preferably methoxy.

Substituted phenyl residues R¹ and R² are preferably substitued asdescribed above in ortho- and/or para-position, more preferably inpara-position.

In another embodiment, R¹ and R² together with the carbon atom to whichthey are attached form a10′,11′-dihydro-2,5′-[5H]dibenzo[a,d]cycloheptene residue.

In one embodiment, the present invention relates to a compound offormula (I) as defined above, wherein R³ and R⁴ are independentlyhydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, perfluoro-loweralkyl, alkanoyl or cyano. Preferred halogen residues R³ and R⁴ arefluoro, chloro and bromo, with fluoro being especially preferred.Preferred lower alkyl residue in R³ and R⁴is methyl. Preferred loweralkoxy residue in R³ and R⁴is methoxy. Preferred perfluoro-lower alkylresidue in R³ and R⁴is trifluoromethyl.

In another preferred embodiment, the present invention relates to acompound of formula (I) as defined above, wherein R³ and R⁴ areindependently hydrogen, hydroxy or halogen, such as fluoro, chloro orbromo. Preferred substituents R³ and R⁴ are hydrogen, and fluoro, withhydrogen being especially preferred.

In one embodiment, the present invention related to compounds of formula(I) as defined above, wherein R⁵ and R⁶ together with the nitrogen atomto which they are attached form a 4-, 5-, 6- or 7-membered monocyclic ora 8-, 9-, 10- or 12-membered bicyclic, saturated or unsaturatedheterocyclic ring which may optionally contain one or two furtherheteroatoms independently selected from O, N and S, said heterocyclicring being optionally mono-, di- or tri-substituted, preferably mono- ordi-substituted, independently, by lower alkyl, lower alkoxycarbonyl,hydroxy lower alkyl, lower alkoxy-lower alkyl, di-lower alkylcarbamoyl,carbamoyl, lower alkylcarbonyl amino, oxo, alkanoyl, amino lower alkyl,hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano,heteroaryl, or by phenyl or phenyl lower alkyl, wherein the phenylmoiety may optionally be mono-, di- or tri-substituted, preferably mono-or di-substituted, independently, by lower alkyl, lower alkoxy, halogen,perfluoro-lower alkyl, hydroxy, alkanoyl or cyano.

In another embodiment, the present invention relates to a compound offormula (I) as defined above, wherein R⁵ and R⁶ together with thenitrogen atom to which they are attached form a 5-, 6- or 7-memberedmonocyclic or a 9- or 10-membered bicyclic, saturated or unsaturatedheterocyclic ring which may optionally contain one or two furtherheteroatoms independently selected from O and N, said heterocyclic ringbeing optionally mono- or di-substituted, independently, by lower alkyl,lower alkoxycarbonyl, hydroxy lower alkyl, alkanoyl, hydroxy, or byphenyl or phenyl lower alkyl, wherein the phenyl moiety may optionallybe mono- or di- substituted, independently, by lower alkyl, loweralkoxy, halogen or perfluoro-lower alkyl.

In still another preferred embodiment, the present invention relates toa compound of formula (I) as defined above, wherein R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a 5- or6-membered monocyclic saturated heterocyclic ring which may optionallycontain one further heteroatom selected from O and S, said heterocyclicring being optionally mono- or di-substituted, independently, by hydroxyor by halogen such as fluoro.

In one embodiment, preferable heterocyclic rings formed by R⁵ and R⁶together with the nitrogen atom to which they are attached arepiperazinyl, morpholino, piperidinyl, piperidin-4-one, pyrrolidinyl,thiomorpholino, azepanyl, 1,2,3,4-tetrahydro-isoquinolinyl,1,2,3,6-tetrahydro-pyridinyl, [1,4]-diazepanyl,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl,2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4yl and3-hydroxy-8-aza-bicyclo[3.2.1.]oct-8-yl, optionally substituted asindicated above, preferably mono-, di- or tri-substituted, preferablymono- or di-substituted, independently, by lower alkyl such as methyland isopropyl; by lower alkoxycarbonyl such as ethoxycarbonyl; byhydroxy lower alkyl such as hydroxymethyl; by lower alkoxy-lower alkylsuch as methoxymethyl; by di-lower alkylcarbamoyl such asdimethylcarbamoyl; by carbamoyl; by lower alkylcarbonyl amino such asacetylamino; by oxo; by dioxo; by alkanoyl such as formyl; by hydroxy;by lower alkoxy such as methoxy and ethoxy; by halogen such as fluoro;by perfluoro-lower alkyl such as trifluoromethyl; by heteroaryl such asunsubstituted pyrazinyl, unsubstituted pyridinyl, pyridinyldisubstituted by chloro and/or trifluoromethyl; or by phenyl or phenyllower alkyl such as benzyl, wherein the phenyl moiety may optionally bemono-, di- or tri-substituted, preferably mono- or di-substituted,independently, by lower alkyl such as methyl, by lower alkoxy such asmethoxy, by halogen such as chloro and fluoro, or by perfluoro-loweralkyl such as trifluoromethyl.

In another embodiment, preferable heterocyclic rings formed by R⁵ and R⁶together with the nitrogen atom to which they are attached arepiperazinyl, morpholino, piperidinyl, piperidin-4-one, pyrrolidinyl,1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,6-tetrahydro-pyridinyl,[1,4]-diazepanyl and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, withpiperazinyl, morpholino and piperidinyl being especially preferred. Inanother preferable embodiment, the heterocyclic ring formed by R⁵ and R⁶together with the nitrogen atom to which they are attached ispiperidinyl.

Further preferable heterocyclic rings formed by R⁵ and R⁶ together withthe nitrogen atom to which they are attached are piperidinyl,morpholino, thiomorpholino and pyrrolidinyl, optionally substituted asindicated above, preferably optionally mono- or di-substituted,independently, by hydroxy or by halogen such as fluoro. Most preferableheterocyclic ring formed by R⁵ and R⁶ together with the nitrogen atom towhich they are attached is morpholino.

In one embodiment, the heterocyclic rings formed by R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached are unsubstituted.

In another embodiment, the heterocyclic rings formed by R⁵ and R⁶together with the nitrogen atom to which they are attached are mono-,di- or tri-substituted, preferably mono- or di-substituted,independently, by lower alkyl such as methyl and isopropyl; by loweralkoxycarbonyl such as ethoxycarbonyl; by hydroxy lower alkyl such ashydroxymethyl; by lower alkoxy-lower alkyl such as methoxymethyl; bydi-lower alkylcarbamoyl such as dimethylcarbamoyl; by carbamoyl; bylower alkylcarbonyl amino such as acetylamino; by oxo; by dioxo; byalkanoyl such as formyl; by hydroxy; by lower alkoxy such as methoxy andethoxy; by halogen such as fluoro; by perfluoro-lower alkyl such astrifluoromethyl; by heteroaryl such as unsubstituted pyrazinyl,unsubstituted pyridinyl, pyridinyl disubstituted by chloro and/ortrifluoromethyl; or by phenyl or phenyl lower alkyl such as benzyl,wherein the phenyl moiety may optionally be mono-, di- ortri-substituted, preferably mono- or di-substituted, independently, bylower alkyl such as methyl, by lower alkoxy such as methoxy, by halogensuch as chloro and fluoro, or by perfluoro-lower alkyl such astrifluoromethyl.

In another embodiment, the heterocyclic rings formed by R⁵ and R⁶together with the nitrogen atom to which they are attached arepreferably mono- or di-substituted, independently, by methyl, propyl,ethoxycarbonyl, hydroxymethyl, formyl, hydroxy, unsubstituted pyrazinyl,unsubstituted pyridinyl, pyridinyl disubstituted by chloro and/ortrifluoromethyl; or by phenyl or phenyl methyl, wherein the phenylmoiety may optionally be mono- or di- substituted, independently, bymethyl, methoxy, chloro, fluoro and/or trifluoromethyl.

In a preferable embodiment, the heterocyclic rings formed by R⁵ and R⁶together with the nitrogen atom to which they are attached areoptionally mono- or di-substituted, independently, by hydroxy or byhalogen such as fluoro.

Substituted 6-membered heterocyclic rings formed by R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached rings are preferablysubstituted at position 4 of the ring; substituted 5-membered rings arepreferably substituted at position 3 of the ring.

In one embodiment, the present invention related to compounds of formula(I) as defined above, wherein R⁵ is hydrogen, lower alkyl, loweralkylsulfonyl, cycloalkyl lower alkyl or hydroxy-lower alkyl. Preferablelower alkyl residues R⁵ are methyl and ethyl, with methyl beingespecially preferred. Preferable lower alkylsulfonyl residue R⁵ isn-butylsulfonyl. Preferable cycloalkyl lower alkyl residue R⁵ iscyclopropylmethyl. Preferable hydroxy-lower alkyl residue R⁵ is2-hydroxyethyl.

In one embodiment, the present invention related to compounds of formula(I) as defined above, wherein R⁶ is Y—R⁸, lower alkyl, lower alkoxy,hydroxy-lower alkyl, lower alkoxy-lower alkyl, loweralkylcarbamoyl-lower alkyl, heterocyclyl, cycloalkyl, phenyl or phenyllower alkyl, wherein the phenyl moiety may optionally be mono-, di- ortri-substituted, preferably mono- or di-substituted, independently, bylower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy,alkanoyl or cyano.

In another embodiment, the present invention related to compounds offormula (I) as defined above, wherein R⁶ is lower alkyl, lower alkoxy,hydroxy-lower alkyl, lower alkoxy-lower alkyl, loweralkylcarbamoyl-lower alkyl, heterocyclyl, cycloalkyl, phenyl or phenyllower alkyl, wherein the phenyl moiety may optionally be mono-, di- ortri-substituted, preferably mono- or di-substituted, independently, bylower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy,alkanoyl or cyano.

Preferable lower alkyl residues R⁶ are ethyl, n-propyl and isopropyl.Preferable lower alkoxy residues R⁶ are tert-butoxy and methoxy.Preferable hydroxy-lower alkyl residue R⁶ is 2-hydroxy-ethyl. Preferablelower alkoxy-lower alkyl residue R⁶ is methoxyethyl. Preferableheterocyclyl residues R⁶ are morpholino, tetrahydrofuranyl andpyrrolidinyl. Heterocyclyl residues R⁶, preferably pyrrolidinyl residueR⁶, may optionally be mono-substituted by lower alkoxy-lower alkyl suchas methoxymethyl. Preferable cycloalkyl residues R⁶ are cyclopropyl,cyclobutyl, cyclopentyl and cycloheptyl. Preferable phenyl lower alkylresidues R⁶ are benzyl and phenylethyl. The phenyl moieties of phenyllower alkyl residues R⁶, preferably of phenylethyl residue R⁶, mayoptionally be mono-substituted by lower alkoxy such as methoxy.Preferable lower alkylcarbamoyl-lower alkyl residue R⁶ is2,2-dimethyl-1-methylcarbamoyl-propyl.

In another embodiment, the present invention relates to compounds offormula (I) as defined above, wherein R⁶ is Y—R⁸.

In still another embodiment, the present invention relates to compoundsof formula (I) as defined above, wherein R⁶ is hydrogen when X is—C(O)—or —SO₂—.

In one embodiment, the present invention relates to a compound offormula (I) as defined above, wherein R⁷ is hydrogen, cyano, halogensuch as fluoro, or lower alkyl such as methyl. In another embodiment, R⁷is cyano, halogen such as fluoro, or lower alkyl such as methyl. Instill another embodiment, the present invention relates to a compound offormula (I) as defined above, wherein R⁷ is hydrogen. Preferably, R⁷ ishalogen, with fluoro being especially preferred.

In another embodiment, the present invention relates to a compound offormula (I) as defined above, wherein R⁸ is phenyl, cycloalkyl,heterocyclyl or heteroaryl.

Preferable cycloalkyl residue R⁸ is cyclohexyl. Preferable lower alkylresdues R⁸ are n-propyl, for example when Y is —C(O)—, methyl andn-butyl (for example when Y is —SO2-). Preferable heterocyclyl residuesR⁸ are morpholino, piperidinyl and azepanyl. Preferable heteroaryresidue R⁸ is pyridinyl.

In a preferrable embodiment, R⁸ is a heterocyclyl residue such asmorpholino, piperidinyl and azepanyl, with piperidinyl being especiallypreferred.

In one embodiment, the present invention relates to compounds of formula(I) as defined above, wherein X is a single bond, —CH₂—, —C(O)—, —SO₂—or —SO₂NH—.

In another embodiment, the present invention relates to compounds offormula (I) as defined above, wherein X is a single bond, R³, R⁴ and R⁷are hydrogen and R¹, R², R⁵ and R⁶ are as defined above.

In a preferred embodiment, the present invention relates to a compoundof formula (I) as defined above, wherein X is —C(O)— or —SO₂—, with—C(O)— being especially preferred.

In another embodiment, the present invention relates to a compound offormula (I) as defined above, wherein Y is —CH₂—, —C(O)—, —NH— or —SO₂—.Preferably, Y is —CH₂— or —NH—.

In a preferable embodiment, the present invention relates to compoundsof formula (I), wherein R¹ and R² are independently phenyl which ismono- or di-substituted, independently, by lower alkoxy such as methoxyor preferably by halogen such as fluoro, chloro and bromo; R³ and R⁴ areeach hydrogen; R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 5- or 6-membered monocyclic saturated heterocyclicring which may optionally contain one further heteroatom selected from Oand S, such as piperidinyl, morpholino, thiomorpholino and pyrrolidinyl,said heterocyclic ring being optionally mono- or di-substituted,independently, by hydroxy or by halogen such as fluoro; R⁷ is halogensuch as fluoro; X is —C(O)—; and pharmaceutically acceptable saltsthereof

Preferred compounds of general formula (I) are those selected from thegroup consisting of:

-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperidine,-   1-(4-Chloro-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine,-   1-(2,3-Dimethyl-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine,-   1-(2,4-Dichloro-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-fluoro-phenyl)-piperazine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(3-chloro-phenyl)-piperazine,-   4-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-morpholine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-phenyl-piperazine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-pyrrolidine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(3-methoxy-phenyl)-piperazine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-methoxy-phenyl)-piperazine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-methoxy-phenyl)-piperazine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-chloro-phenyl)-piperazine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-fluoro-phenyl)-piperazine,-   2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonic acid phenethyl-amide,-   Benzo[1,3]dioxol-5-yl-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine,-   4-Benzyl-1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperidine,-   2-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline,-   2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonic acid benzyl-methyl-amide,-   2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonic acid benzylamide,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-methyl-[1,4]diazepane,-   1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-[1,4]diazepane,-   2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonic acid phenylamide,-   2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonic    acid[2-(4-methoxy-phenyl)-ethyl]-amide,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-methyl-piperazine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine,-   4-(4-Chloro-phenyl)-1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-1,2,3,6-tetrahydro-pyridine,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-phenyl-1,2,3,6-tetrahydro-pyridine,-   racemic    1-[2-(2-Chloro-phenyl)-2-(4-methoxy-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(2-Chloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(2-Chloro-phenyl)-2-p-tolyl-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(4-Chloro-phenyl)-2-p-tolyl-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   1-[2,2-Bis-(4-chloro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(4-Fluoro-phenyl)-2-phenyl-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(4-Methoxy-phenyl)-2-phenyl-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(4-Chloro-phenyl)-2-p-tolyl-benzo[1,3]dioxole-5-sulfonyl]-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine,-   racemic    1-[2-(4-Chloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(2,4-Dichloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   1-[2,2-Bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(3-Chloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    1-[2-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   racemic    (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(3-hydroxy-pyrrolidin-1-yl)-methanone,-   4-(2,2-Diphenyl-benzo[1,3]dioxole-5-carbonyl)-piperazine-1-carbaldehyde,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-hydroxymethyl-piperidin-1-yl)-methanone,-   (1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-isopropyl-piperazin-1-yl)-methanone,-   1-(2,2-Diphenyl-benzo[1,3]dioxole-5-carbonyl)-piperidin-4-one,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-hydroxy-piperidin-1-yl)-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-pyrrolidin-1-yl-methanone,-   racemic    1-(2,2-Diphenyl-benzo[1,3]dioxole-5-carbonyl)-piperidine-3-carboxylic    acid ethyl ester,-   [4-(5-Chloro-2-methoxy-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-m-tolyl-piperazin-1-yl)-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-o-tolyl-piperazin-1-yl)-methanone,-   racemic    1-(2,2-Diphenyl-benzo[1,3]dioxole-5-carbonyl)-piperidine-2-carboxylic    acid ethyl ester,-   [4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone,-   [4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone,-   racemic    (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(3-hydroxymethyl-piperidin-1-yl)-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone,-   (4-Fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone,-   (4-Fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   (4-Fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   (4,7-Dichloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   (4,7-Dichloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   (4,7-Dichloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone,-   (7-Bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone,-   (7-Bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   (7-Bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   (7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone,-   1-(2,2-Diphenyl-benzo[1,3]dioxol-5-ylmethyl)-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine,    and pharmaceutically acceptable salts thereof.

Further preferred compounds of general formula (I) are those selectedfrom the group consisting of:

-   N-(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-benzenesulfonamide,-   N,N-bis(methylsulfonyl)-2,2-diphenyl-1,3-benzodioxol-5-amine,-   N,N-bis(butylsulfonyl)-2,2-diphenyl-1,3-benzodioxol-5-amine,-   Cyclohexanecarboxylic acid    (2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide,-   Butane-1-sulfonic acid (2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide,-   N-(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-butyramide,-   Morpholine-4-carboxylic acid    (2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide,-   Piperidine-1-sulfonic acid    (2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide,-   Piperidine-1-carboxylic acid    (2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide,-   [2-(4-Chloro-phenyl)-2-(2-fluoro-4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   4-[2-(4-Chloro-phenyl)-2-(2-fluoro-4-methoxy-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine,-   [2-(4-Methoxy-phenyl)-2-(3-nitro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   4-[2-(4-Methoxy-phenyl)-2-(3-nitro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine,-   4-[2-(4-Methoxy-phenyl)-5-(morpholine-4-carbonyl)-benzo[1,3]dioxol-2-yl]-benzonitrile,-   4-[2-(4-Methoxy-phenyl)-5-(morpholine-4-sulfonyl)-benzo[1,3]dioxol-2-yl]-benzonitrile,-   [2-(2-Fluoro-4-methoxy-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   4-[2-(2-Fluoro-4-methoxy-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine,-   (6-Fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [6-Fluoro-2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2-(2-Chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   (6-Fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   [6-Fluoro-2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2-Chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   (6-Fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone,-   [6-Fluoro-2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxol-5-yl]-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone,-   [2-(2-Chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-fluoro-phenyl)-piperazin-1-yl]-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   (6-Methyl-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   (6-Bromo-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   (+)-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   (−)-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   (6-Chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   (6-Chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid ethyl-methyl-amide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid methyl-propyl-amide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid azepan-1-ylamide,-   Azetidin-1-yl-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-methanone,-   Azepan-1-yl-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-dioxol-yl]-methanone,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid (2,2-dimethyl-1-methylcarbamoyl-propyl)-amide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2S-methoxymethyl-pyrrolidin-1-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2R-hydroxymethyl-pyrrolidin-1-yl)-methanone,-   1-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carbonyl]-pyrrolidine-2R-carboxylic    acid dimethylamide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid cyclobutylamide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid morpholin-4-ylamide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-methanone,-   1-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carbonyl]-pyrrolidine-2S-carboxylic    acid amide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid tert-butoxy-amide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid cyclopentylamide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid (tetrahydro-furan-2-ylmethyl)-amide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid isopropylamide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid pyrrolidin-1-ylamide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid methoxy-methyl-amide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3R-hydroxy-pyrrolidin-1-yl)-methanone,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid bis-cyclopropylmethyl-amide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-fluoro-piperidin-1-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-hydroxymethyl-piperidin-1-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone,-   N-{1-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carbonyl]-pyrrolidin-3S-yl}-acetamide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid cycloheptylamide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid N′-pyridin-2-yl-hydrazide,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid (2S-methoxymethyl-pyrrolidin-1-yl)-amide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2R-methoxymethyl-pyrrolidin-1-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3S-hydroxy-pyrrolidin-1-yl)-methanone,-   N-{1-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carbonyl]-pyrrolidin-3R-yl}-acetamide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2S-hydroxymethyl-pyrrolidin-1-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo    1,3]dioxol-5-yl]-morpholin-4-yl-methanethione,-   [2-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   6-(Morpholine-4-carbonyl)-2,2-diphenyl-benzo[1,3]dioxole-5-carbonitrile,-   [2-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(4-bromo-phenyl)-6-fluoro-benzo[1,3    ]dioxol-5-yl]-morpholin-4-yl-methanone,-   4-[2,2-Bis-(4-cyano-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carbonyl]-morpholine,-   4-[2-(4-Bromo-phenyl)-5-fluoro-6-(morpholine-4-carbonyl)-benzo[1,3]dioxol-2-yl]-benzonitrile,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [6-Chloro-2,2-bis-(2,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2-Chloro-4-fluoro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [6-Fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   4-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-morpholine,-   4-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3S-ethoxy-pyrrolidin-1-yl)-methanone,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid (1R-phenyl-ethyl)-amide,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(1-oxo-thiomorpholin-4-yl)-methanone,-   [2,2-Bis-(2-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [6-Fluoro-2,2-bis-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [6-Fluoro-2,2-bis-(3-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2-Chloro-4-fluoro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-yl-methanone,-   [2,2-Bis-(3,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(3,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(3-hydroxy-pyrrolidin-yl)-methanone,-   [2,2-Bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone,-   2,2-Bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylic    acid ethyl-methyl-amide,-   2,2-Bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylic    acid bis-(2-hydroxy-ethyl)-amide,-   [2,2-Bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone,-   [2,2-Bis-(2-chloro-4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(3,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(2,5-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(2-chloro-4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(2-chloro-4-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [6-Chloro-2,2-bis-(2-chloro-4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid amide,-   [2,2-Bis-(4-bromo-2-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3,4-cis-dihydroxy-pyrrolidin-1-yl)-methanone,-   [2,2-Bis-(2,3-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [6-Fluoro-2,2-bis-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(2-chloro-4,5-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   4-[2,2-Bis-(2-chloro-4-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-morpholine,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-fluoro-piperidin-1-yl)-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(3S-hydroxy-pyrrolidin-1-yl)-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(2S-hydroxymethyl-pyrrolidin-1-yl)-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(2S-methoxymethyl-pyrrolidin-1-yl)-methanone,-   (6-Chloro-2,2-di-p-tolyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   4-[{6-Chloro-10′,11′-dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cyclohepten]-5-yl}carbonyl]-morpholine,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-fluoro-piperidin-1-yl)-methanone,-   (4,4-Difluoro-piperidin-1-yl)-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone,-   (3S-Ethoxy-pyrrolidin-1-yl)-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-[(S)-(2-methoxymethyl-pyrrolidin-1-yl)]-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-[(S)-2-hydroxymethyl-pyrrolidin-1-yl]-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-[(S)-3-hydroxy-pyrrolidin-1-yl]-methanone,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone,-   4-[2,2-Bis-(2-chloro-4,5-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-morpholine,-   (2,2-Di-p-tolyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone,-   (2,2-Di-p-tolyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   4-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine,-   4-(6-Fluoro-2,2-di-p-tolyl-benzo[1,3]dioxole-5-sulfonyl)-morpholine,-   1-{6-Fluoro-10′,11′-dihydrospiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}sulfonyl]-piperidine,-   4-{6′-Fluoro-10′,11′-dihydrospiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}sulfonyl]-morpholine,-   4-[{10′,11′-Dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}carbonyl]-morpholine,-   1-[{10′,11′-dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}carbonyl]-piperidine,-   [6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3-methoxy-piperidin-1-yl)-methanone,-   1-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidine,-   1-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   4-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-thiomorpholine,-   1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   1-[2,2-Bis-(2-chloro-4-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidine,-   1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-4-fluoro-piperidine,-   1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-4,4-difluoro-piperidine,-   1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-4-trifluoromethyl-piperidine,-   4-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-thiomorpholine,-   1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-2S-methoxymethyl-pyrrolidine,-   2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonic    acid (2S-methoxymethyl-pyrrolidin-1-yl)-amide,-   {1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidin-2S-yl}-methanol,-   1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidin-3S-ol,-   1-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-piperidin-4-ol,-   1-[2,2-Bis-(2-chloro-4,5-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   4-[{6-Fluoro-10′,11′-dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cyclohepten]-5-yl}-carbonyl]-morpholine,-   (6-Fluoro-2,2-di-p-tolyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,-   1-(6-Fluoro-2,2-di-p-tolyl-benzo[1,3]dioxole-5-sulfonyl)-piperidine,-   [6-Fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [6-Fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone,-   4-Fluoro-1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   4,4-Difluoro-1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine,-   1-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-4-trifluoromethyl-piperidine,-   1-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-2-methoxymethyl-pyrrolidine,-   1-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidin-3S-ol,-   1-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidin-4-ol,-   [2,2-Bis-(3-chloro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-bis-(4-cyano-2-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   6-Fluoro-[2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-[(S)-3-hydroxy-pyrrolidin-1-yl)]-methanone,-   6-Fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid ethyl-methyl-amide,-   6-Fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic    acid (2-methoxy-ethyl)-methyl-amide,-   [2,2-Bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(3-bromo-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [6-Fluoro-2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(3-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(3-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,    and pharmaceutically acceptable salts thereof.

Especially preferred compounds of general formula (I) are those selectedfrom the group consisting of:

-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   (+)-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   (−)-[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-fluoro-piperidin-1-yl)-methanone,-   [2-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [2,2-Bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone,-   [2,2-Bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone,-   [2,2-Bis-(4-bromo-2-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4,4-difluoro-piperidin-1-yl)-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone,-   [2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(3S-hydroxy-pyrrolidin-1-yl)-methanone,    and pharmaceutically acceptable salts thereof

The present invention also relates to a process for the manufacture ofcompounds of formula (I) as defined above. The compounds of formula (I)can be manufactured by the methods given below, by the methods given inthe Examples or by analogous methods. Appropriate reaction conditionsfor the individual reaction steps are known to the person skilled in theart. Starting materials are either commercially available or can beprepared by methods analogous to the methods given below or in theExamples or by methods known in the art.

The compound of formula (I) wherein R¹ to R⁷ and X are as previouslydefined may be prepared using the general methods depicted in Scheme 1as further described below.

According to Scheme 1, a catechol intermediate of formula A can beketalized with a bis-substituted dichloromethane derivative of formula Bin an inert solvent (e.g. toluene or pyridine) or neat, with or withoutthe presence of a base (e.g. pyridine) at elevated temperature(e.g. >100° C.) to yield product I. Alternatively, a compound of formula(I) may be prepared by reacting the catechol intermediate of formula Awith a ketone of formula C at elevated temperature (e.g. >150° C.) neator in an inert solvent (e.g. toluene) with or without the removal ofwater by distillation, azeotropic distillation or addition of dryingagents (e.g. molecular sieves or 2,2-dimethoxypropane) by methods knownin the art (see e.g. T. R. Kelly, A. Szabados, Y.-J. Lee, J. Org. Chem.62 (2) (1997) 428).

Alternatively, a compound of formula (I) may be prepared by reacting thecatechol intermediate of formula A with a thioketone of formula (C′)neat or in an inert solvent (e.g. acetonitrile) with or without thepresence of a base (e.g. triethylamine) with a metal salt (e.g. Cu¹) bymethods known in the art (see e.g. I. Shibuya, E. Katoh, Y. Gama, A.Oishi, Y. Taguchi and T. Tsuchiya, Heterocycles, 43 (1996) 851).Compounds of formula (I) wherein X is —CH₂— can also be obtained byreduction of a corresponding compound of formula (I) wherein X is —CO—by means known in the art.

The bis-substituted dichloromethane derivatives of formula B can beeasily prepared by methods known in the art from the correspondingketone by reaction with thionyl chloride in the presence of DMF oranother N-formylated agent, by reaction with phosphorus pentachloride atelevated temperature (e.g. >100° C.) with or without the presence of asuitable solvent (e.g. phosphorus oxide chloride), by electrophilicaromatic substitution of the trifluoromethyl derivative E with a benzenederivative of formula D in the presence of a Lewis acid (e.g. aluminiumtrichloride) in an inert solvent (e.g. 1,2-dichloroethane) (e.g. R. K.Ramchandani, R. D. Wakharkar, A. Sudalai, Tetrahedron Lett. 37 (23)(1996) 4063), by chlorination of a bisarylmethane derivative (e.g. U.S.Pat. No. 5,578,737 or W. Deuschel, Helv. Chim. Acta 34 (1951) 2403) orin case of symmetrically bis-substituted dichloromethane derivatives offormula B by electrophilic aromatic substitution of a benzene derivativewith tetrachloromethane in the presence of a Lewis acid (e.g. AlCl₃) inan inert solvent (e.g. 1,2-dichloroethane) (see e.g. J. P. Picard, C.Kearns, Can. J. Res. 28 (1950) 56).

Catechols of formula A can be easily prepared from the correspondingdiphenylmethylene protected ketals of formula (Ia) by treatment with anacid (e.g. trifluoroacetic acid) in a suitable inert solvent (e.g.methylene chloride) or by treatment with an acid (e.g. trifluoroaceticacid) in the presence of a suitable reducing agent (e.g.triethylsilane), neat or with a suitable inert solvent (e.g. methylenechloride). Alternatively, a catechol of formula A can be easily preparedfrom a corresponding bis-benzyl protected catechol of formula (A′) byreduction (e.g hydrogenation in the presence of a suitable catalyst(e.g. palladium on carbon)) by means known in the art). Alternatively acatechol derivative of formula F can be coupled with an appropriateamine in a suitable inert solvent (e.g. DMF, methylene chloride,pyridine or THF) in the presence of a base (e.g. triethyl amine). Eitherthe corresponding acid chlorides (X═CO, Z═Cl) respectively thecorresponding sulfonyl chlorides (X═SO₂, Z═Cl) or the correspondingcarboxylic acids (X═CO, Z═OH) after activation with an appropriatecoupling agent (e.g. carbonyldiimidazole) are used for the preparationof catechols of formula A by methods known in the art. Compounds offormula (A) wherein X is —CH₂— can be obtained by reduction of acorresponding compound of formula (A) wherein X is —CO— by means knownin the art.

Compounds of formula G can be coupled with an appropriate amine in asuitable inert solvent (e.g. DMF, methylene chloride, pyridine or THF)in the presence of a base (e.g. triethyl amine) to yield benzodioxolesof formula (I). Either the corresponding acid chlorides (X═CO, Z═Cl)respectively the corresponding sulfonyl chlorides (X═SO₂, Z═Cl) or thecorresponding carboxylic acids (X═CO, Z═OH) after activation with anappropriate coupling agent (e.g. carbonyldiimidazole) are used for thepreparation of benzodioxoles of formula (I) by methods known in the art.

Benzodioxoles of formula (I)in which X is a single bond may also beprepared according to Scheme 5 above by coupling an aniline of formula Jwith a compound of formula K in a suitable inert solvent (e.g. DMF,methylene chloride, pyridine or THF) in the presence of a base (e.g.triethyl amine) to yield benzodioxoles of formula (Ia). Benzodioxoles offormula (Ia) may then be further coupled with a compound of formula K′in a suitable inert solvent (e.g. DMF, methylene chloride, pyridine orTHF) in the presence of a base (e.g. triethyl amine) to yieldbenzodioxoles of formula (Ib). Compounds of formulae K and K′ may beeither the corresponding acid chlorides, respectively the correspondingsulfonyl chlorides, respectively the corresponding carbamoyl chlorides,respectively the corresponding sulfamoyl chlorides or the correspondingcarboxylic acids of R⁵ and R⁶, respectively, after activation with anappropriate coupling agent (e.g. carbonyldiimidazole).

The invention further relates to compounds of formula (I) as definedabove, when manufactured according to a process as defined above.

Some compounds of formula (I) may possess asymmetric centres and aretherefore capable of existing in more than one stereoisomeric form. Theinvention thus also relates to compounds in substantially pure isomericform at one or more asymmetric centres as well as mixtures, includingracemic mixtures, thereof. Such isomers may be prepared by asymmetricsynthesis, for example using chiral intermediate, or mixtures may beresolved by conventional methods, eg., chromatography (chromatographywith a chiral adsorbent or eluant), or use of a resolving agent.

It will be appreciated, that the compounds of general formula (I) inthis invention may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundin vivo.

As described above, the compounds of formula (I) or pharmaceuticallyacceptable salts thereof can be used as medicaments for the treatmentand/or prophylaxis of diseases which are associated with the modulationof the CB1 receptors.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutic active substances, particularly as therapeutic activesubstances for the treatment and/or prophylaxis of diseases which areassociated with the modulation of CB1 receptors.

In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are associated with themodulation of CB1 receptors, which method comprises administering acompound as defined above to a human being or animal.

The invention further relates to the use of compounds as defined abovefor the treatment and/or prophylaxis of diseases which are associatedwith the modulation of CB1 receptors.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprophylaxis of diseases which are associated with the modulation of CB1receptors. Such medicaments comprise a compound as defined above.

In this context, the expression ‘diseases associated with modulation ofCB1 receptors' means diseases which can be treated and/or prevented bymodulation of CB1 receptors. Such diseases encompass, but are notlimited to, psychic disorders, especially anxiety and anxiety disorders,psychosis, schizophrenia, depression, substance abuse disordersincluding abuse of psychotropes, for example for the abuse and/ordependence of substances, including alcohol dependency and nicotinedependency, neuropathies, migraine, stress, epilepsy, dyskinesias,Parkinson's disease, amnesia, memory and cognitive disorders, seniledementia, Alzheimer's disease, eating disorders, obesity, diabetes typeII or non insulin dependent diabetes (NIDD), gastrointestinal diseases,vomiting, diarrhea, urinary disorders, cardiovascular disorders,infertility disorders, inflammations, infections, cancer,demyelinisation related disorders, neuroinflammation, in particular inatherosclerosis, or the Guillain-Barré syndrome, viral encephalitis,cerebral vascular incidents and cranial trauma.

In a preferable aspect, the expression ‘diseases associated withmodulation of CB1 receptors’ relates to eating disorders, obesity,diabetes type II or non insulin dependent diabetes (NIDD),neuroinflammation, diarrhea, abuse and/or dependence of a substances,including alcohol dependency and nicotine dependency. In a morepreferable aspect, the said term related to eating disorders, obesity,diabetes type II or non insulin dependent diabetes (NIDD), abuse and/ordependence of a substances, including alcohol dependency and nicotinedependency, with obesity being especially preferred.

It is a further preferred object to provide a method of treatment orprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM) in a human which comprises administration of a therapeuticallyeffective amount of a compound according to formula (I) in combinationor association with a therapeutically effective amount of a lipaseinhibitor, particularly, wherein the lipase inhibitor is orlistat. Alsoan object of the invention is the method as described above for thesimultaneous, separate or sequential administration of a compoundaccording to formula (I) and a lipase inhibitor, particularlytetrahydrolipstatin.

It is a further preferred object to provide a method for the treatmentor prevention of obesity and obesity related disorders which comprisesadministration of a therapeutically effective amount of a compoundaccording to formula (I) in combination or association with atherapeutically effective amount of other drugs for the treatment ofobesity or eating disorders so that together they give effective relief.Suitable other drugs include but are not limited to anorectic agents,lipase inhibitors and selective serotonin reuptake inhibitors (SSRI).Combinations or associations of the above agents may be encompassingseparate, sequential or simultaneous administration.

Preferable lipase inhibitor is tetrahydrolipstatin.

Suitable anorectic agents of use in combination with a compound of thepresent invention include, but are not limited to, aminorex,amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex,cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine, andpharmaceutically acceptable salts thereof.

Most preferable anorectic agents are sibutramine and phentermine.

Suitable selective serotonin reuptake inhibitors of use in combinationwith a compound of the present invention include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Demonstration of additional biological activities of the compounds ofthe present invention may be accomplished through in vitro, ex vivo, andin vivo assays that are well known in the art. For example, todemonstrate the efficacy of a pharmaceutical agent for the treatment ofobesity-related disorders such as diabetes, Syndrome X, oratherosclerotic disease and related disorders such ashypertriglyceridemia and hypercholesteremia, the following assays may beused.

Method for Measuring Blood Glucose Levels

db/db mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean blood glucose levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 7 to 14 days. At this point, the animals are bled again by eye ortail vein and blood glucose levels are determined.

Method for Measuring Triglyceride Levels

hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean serum triglyceride levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 7 to 14 days. The animals are then bled again by eye or tail vein,and serum triglyceride levels are determined.

Method for Measuring HDL-Cholesterol Levels

To determine plasma HDL-cholesterol levels, hApoAl mice are bled andgrouped with equivalent mean plasma HDL-cholesterol levels. The mice areorally dosed once daily with vehicle or test compound for 7 to 14 days,and then bled on the following day. Plasma is analyzed forHDL-cholesterol.

In addition, to demonstrate CNS activities of the compounds of thepresent invention, the following in vivo assays may be used.

Method for Testing Task Learning and Spatial Memory

The Morris Water Maze is routinely used to assess task learning andspatial memory (Jaspers et al., Neurosci. Lett. 117:149-153, 1990;Morris, J. Neurosci. Methods 11:47-60, 1984). In this assay, animals areplaced in a water pool which is divided into quadrants. One platform ishidden in one of the quadrants. The animal is placed in the water pooland is expected to locate the hidden platform within a predeterminedtime. During a number of training trials, the animal learns the locationof the platform and escape from the pool. The animal receives multipletrials in this task. Total distance traveled, number of trials to locateplatform, latency to find platform, and the swimming path is recordedfor each animal. The animal's learning ability is measured by the lengthof time or number of trials required to find the hidden platform. Memorydeficit or improvement is determined by the number of trials or thelatency to find the platform at predetermined delay time afteracquisition. Leaning and memory may be measured by the number of timesthat the animal crosses the quadrant where the platform was locatedduring the acquisition phase.

Method for Testing Drug Dependence

Self-administration in animals is a predictor of a compound's abusepotential in humans. Modifications to this procedure may also be used toidentify compounds that prevent or block the reinforcing properties ofdrugs that have abuse potential. A compound that extinguishes theself-administration of a drug may prevent that drug's abuse or itsdependence. (Ranaldi et al., Psychopharmacol. 161:442-448, 2002;Campbell et al., Exp. Clin. Psychopharmacol. 8:312-25, 2000). In aself-administration test, animals are placed in the operant chamberscontaining both an active and inactive lever. Each response on theactive lever produces an infusion of either the test compound or a drugknown to be self-administered. Presses on the inactive lever have noeffect, but are also recorded. Animals are then trained toself-administer compound/drug over a set period of time by having drugaccess during each daily session. Illumination of the chamber houselight signals the beginning of the session and the availability of thecompound/drug. When the session ends, the house light is turned offInitially, a drug infusion occurs with every press of the active lever.Once lever-pressing behavior has been established, the number of pressesto produce a drug infusion is increased. After stable compound/drugself-administration is obtained, the effect of a second compound on thedrug-reinforced behavior may be evaluated. Administration of this secondcompound prior to the session can either potentiate, extinguish, orproduce no change to the self-administrating behavior.

The following tests were carried out in order to determine the activityof the compounds of formula (I).

The affinity of the compounds of the invention for cannabinoid CB1receptors was determined using membrane preparations of human embryonickidney (HEK) cells in which the human cannabis CB1 receptor istransiently transfected using the Semliki Forest Virus system inconjunction with [3H]-CP-55,940 as radioligand. After incubation of afreshly prepared cell membrane preparation with the [3H]-ligand, with orwithout addition of compounds of the invention, separation of bound andfree ligand was performed by filtration over glassfiber filters.Radioactivity on the filter was measured by liquid scintillationcounting.

The affinity of the compounds of the invention for cannabinoid CB2receptors was determined using membrane preparations of human embryonickidney (HEK) cells in which the human cannabis CB2 receptor istransiently transfected using the Semliki Forest virus system inconjunction with [3H]-CP-55,940 as radioligand. After incubation of afreshly prepared cell membrane preparation with the [3H]-ligand, with orwithout addition of compounds of the invention, separation of bound ofbound and free ligand was performed by filtration over glassfiberfilters. Radioactivity on the filter was measured by liquidscintillation counting.

The cannabinoid CB1 antagonistic activity of compounds of the inventionwas determined by functional studies using CHO cells in which humancannabinoid CB1 receptors are stably expressed (see M. Rinaldi-Carmonaet. al., J. Pharmacol. Exp. Ther. 278 (1996) 871). The stable expressionof the human cannabinoid receptor in cell systems was first described inNature 1990, 346, 561-564 (CB1) and Nature 1993, 365, 61-65 (CB2)respectively. Adenylyl cyclase was stimulated using forskolin andmeasured by quantifying the amount of accumulated cyclic AMP.Concomitant activation of CB1 receptors by CB1 receptor agonists (e.g.CP-55,940 or (R)-WIN-55212-2) can attenuate the forskolin-inducedaccumulation of cAMP in a concentration dependent manner. This CB1receptor mediated response can be antagonised by CB1 receptorantagonists such as the compounds of the invention.

The compounds of formula (I) show an excellent affinity for the CB1receptor, determined with the experimental conditions described inDevane et.al. Mol. Pharmacol. 34 (1988) 605-613. The compounds of thepresent invention or their pharmaceutically acceptable salts areantagonists and selective for the CB1 receptor with affinites below IC₅₀=2 μM, preferably 1 nM to 100 nM. They exhibit at least a 10 foldselectivity against the CB2 receptor.

Compound of Example IC₅₀ [μM] 39 <2 μM 46 <2 μM 18 <2 μM 65 <2 μM 4 <2μM 20 <2 μM 22 <2 μM 75 <2 μM 108 <2 μM 164 <2 μM 234 <2 μM 271 <2 μMEffect of CB1 Receptor Antagonist/Inverse Agonist on CP 55,940-InducedHypothermia in NMRI MiceAnimals

Male NMRI mice were used in this study and were obtained from ResearchConsulting Company Ltd (RCC) of Füllinsdorf (Switzerland). Mice,weighing 30-31 g were used in this study. Ambient temperature isapproximately 20-21° C. and relative humidity 55-65%. A 12 hourlight-dark cycle is maintained in the rooms with all tests beingperformed during the light phase. Access to tap water and food are adlibitum.

Method

All measurements were made between 12:00 am and 5:00 pm. Mice werebrought in this environment and habituated for at least two hours beforethe start of the experiment. They had always free access to food andwater. For each dose, 8 mice were used. Rectal body temperaturemeasurements were recorded by mean of a rectal probe (RET2 of Physitemp)and digital thermometer (Digi-sense n°8528-20 of Cole Parmer, ChicagoUSA). The probe was inserted about 3.5 cm in each mouse.

The body temperature was taken 15 min before administration of eitherVehicle or CB1 receptor antagonist/inverse agonist. 30 or 90 min afteri.p. or p.o. administration of this compound, respectively, rectal bodytemperature was recorded in order to evaluate any influence of thecompound itself. The CB receptor agonist CP 55,940 (0.3 mg/kg) wasimmediately administered intravenously, then 20 min after i.v.administration of CP 55940, body temperature was again measured.

The in vivo activity of compounds of formula (1) was assessed for theirability to regulate feeding behaviour by recording food consumption infood deprived animals.

Rats were trained to have access to food for 2 h per day and were fooddeprived for 22 h. When they were trained under this schedule, theamount of food taken every day during these 2h food intake session wasconsistent day after day.

To test the ability of compounds of formula (1) to decrease food intake,8 animals were used in a cross-over study. Rats were individually housedin Plexiglas boxes with a grid on the floor and a paper was placed belowthe cage floor to collect any spillage. A food dispenser (becher) filledwith a pre-weighed amount of food was presented to them for 2 h. At theend of the food intake session, rats returned to their home cage. Eachrat was weighed before the start of the experiment and the amount offood consumed during this 2 h food intake session was recorded. Eithervarious doses of test compound or vehicle was administered orally 60 minbefore the 2 h food intake session. A positive control Rimonabant(SR141716) was included in the experiment. An Anova analysis withrepeated measures was used followed by a posthoc test StudentNeumann-Keuls. * P <0.05 compared to Saline-treated rats.

Furthermore the utility of compounds of formula (1) in diseases ordisorders may be demonstrated in animal disease models that have beenreported in the literature. The following are examples of such animaldisease models: a) reduction of sweet food intake in marmosets(Behavioural Pharm, 1998, 9,179-181); b) reduction of sucrose andethanol intake in mice (Psychopharm. 1997, 132, 104-106); c) increasedmotor activity and place conditioning in rats (Psychopharm. 1998, 135,324-332; Psychopharmacol 2000, 151: 25-30); d) spontaneous locomotoractivity in mice (J. Pharm. Exp. Ther. 1996, 277, 586-594); e) reductionin opiate self-administration in mice (Sci. 1999, 283, 401-404);

The compounds of formula (I) and/or their pharmaceutically acceptablesalts can be used as medicaments, e.g. in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. They canbe administered, for example, perorally, e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatine capsules, solutions,emulsions or suspensions, rectally, e.g. in the form of suppositories,parenterary, e.g. in the form of injection solutions or infusionsolutions, or topically, e.g. in the form of ointments, creams or oils.Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula (I) and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 1000 mg,especially about 1 to 100 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g. in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 1-100 mg, of a compound of formula (I).

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES

MS=mass spectrometry, ISP=ion spray (positive ion), m.p.=melting point,aq.=aqueous, DMSO=dimethylsulfoxide, NMR=nuclear magnetic resonancespectroscopy, EDCI=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride, HPLC=high performance liquid chromatography.

Example 1 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperidine

2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (3.36 g, 9 mmol) wasdissolved in methylene chloride (135 ml). Piperidine (1.33 ml, 13.5mmol) and ethyldiisopropyl amine (2.3 ml, 13.5 mmol) were added at roomtemperature. The reaction was stirred at room temperature overnight andwashed twice with 1N aqueous HCl solution, twice with 1N aqueous NaOHsolution and once with brine. The organic layer was dried over sodiumsulfate and filtered. The solvent was evaporated and the residue waspurified by column chromatography (4/1 hexane/ethyl acetate eluant). Theproduct was suspended in diethyl ether and filtered to yield a whitecrystalline solid (1.98 g, 52 %). m.p.: 163-164° C.

Preparation of 2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride

The sulfonyl chloride derivative was prepared according to literatureprocedures (WO9218490, EP544166).

Method A

Method A is a general method for the preparation of2,2-diphenyl-benzo[1,3]dioxole-5-sulfonamides starting from commerciallyavailable amines:

2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (93 mg, 0.25 mmol)was dissolved in pyridine (1 ml). The appropriate amine (0.25 mmol) wasadded and the reaction was heated to 60° C. overnight. Water was addedand solids respectively oils separated. The aqueous phase was decantedand the residue was stirred with acetonitrile. A solid precipitated,which was filtered off and washed with a little acetonitrile to yieldafter drying at high vacuum the product.

The following examples were prepared using the general method A:

Example 2 Preparation of1-(4-chloro-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine

Using 4-(4-chlorophenyl)piperazine (49.2 mg, 0.25 mmol) as an amine, thetitle compound was obtained as a white solid (27 mg, 20%).

MS (ISP): 533.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.44-7.56 (m,10H), 7.41 (s, 1H), 7.37 (d, 1H), 7.32 (d, 1H), 7.26 (d, 2H), 6.90 (d, 2H), 3.16-3.19 (m, 4H), 2.98-3.02 (m, 4H).

Example 3 Preparation of1-(2,3-dimethyl-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine

Using 4-(2,3-dimethylphenyl)piperazine hydrochloride (56.7 mg, 0.25mmol) as an amine, the title compound was obtained as a white solid (8mg, 6%).

MS (ISP): 527.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.45-7.60 (m,5H), 7.47-7.55 (m, 5H), 7.46 (s, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 7.01(t, 1H), 6.89 (m, 2 H), 3.00-3.12 (m, 4H), 2.82-2.88 (m, 4H), 2.17 (s,3H), 2.02 (s, 3H).

Example 4 Preparation of1-(2,4-dichloro-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine

Using 4-(2,4-dichlorophenyl)piperazine hydrochloride (66.9 mg, 0.25mmol) as an amine, the title compound was obtained as a yellow solid (32mg, 23%).

MS (ISP): 567.1 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.45-7.60 (m,10H), 7.42 (s, 1H), 7.34-7.39 (m, 4H), 7.31 (d, 1H), 7.16 (d, 1H),3.00-3.08 (m, 8H).

Example 5 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-fluoro-phenyl)-piperazine

Using 4-(4-fluorophenyl)piperazine (45.1 mg, 0.25 mmol) as an amine, thetitle compound was obtained as a light yellow solid (66.4 mg 51%).

MS (ISP): 517.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.51-7.56 (m,4H), 7.45-7.49 (m, 6H), 7.41 (s, 1H), 7.37 (d, 1H), 7.29 (d, 1H), 7.02(t, 1H), 6.90-6.94 (m, 1H), 3.11 (m, 4H), 3.01 (m, 4H).

Example 6 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(3-chloro-phenyl)-piperazine

Using 4-(3-chlorophenyl)piperazine (49.2 mg, 0.25 mmol) as an amine, thetitle compound was obtained as a light yellow solid (91.4 mg, 68%).

MS (ISP): 533.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.48-7.56 (m,4H), 7.44-7.48 (m, 6H), 7.41 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.19(t, 1H), 6.82 (d, 1H), 6.79 (d, 1H), 3.23 (m, 4H), 3.00 (m, 4H).

Example 7 Preparation of4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-morpholine

Using morpholine (21.8 mg, 0.25 mmol) as an amine, the title compoundwas obtained as a white solid (51.1 mg 48%).

MS (ISP): 424.4 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.52-7.57 (m,4H), 7.46-7.49 (m, 6H), 7.37 (s, 1H), 7.33 (d, 1H), 7.29 (d, 1H), 3.61(m, 4H), 2.86 (m, 4H).

Example 8 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-phenyl-piperazine

Using 4-phenylpiperazine (40.6 mg, 0.25 mmol) as an amine, the titlecompound was obtained as a light yellow solid (78.7 mg, 63%).

MS (ISP): 499.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.52-7.56 (m,4H), 7.44-7.48 (m, 6H), 7.41 (s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 7.19(t, 2H), 6.89 (d, 2H), 6.77 (t, 1H), 3.17 (m, 4H), 3.02 (m, 4H).

Example 9 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-pyrrolidine

Using pyrrolidine (17.8 mg, 0.25 mmol) as an amine, the title compoundwas obtained as a white solid (67.8 mg, 67%).

MS (ISP): 408.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.53-7.57 (m,4H), 7.43-7.49 (m, 7H), 7.39 (d, 1H), 7.25(d, 1H), 3.12 (m, 4H), 1.64(m, 4H).

Example 10 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(3-methoxy-phenyl)-piperazine

Using 4-(3-methoxyphenyl)piperazine dihydrochloride (66.3 mg, 0.25 mmol)as an amine, the title compound was obtained as a white solid (75.9 mg,58%).

MS (ISP): 529.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.52-7.56 (m,4H), 7.44-7.48 (m, 6H), 7.41 (s, 1H), 7.37 (d, 1H), 7.29 (d, 1H), 7.08(t, 1H), 6.48 (d, 1H), 6.42 (s, 1H), 6.38 (d, 1H), 3.68 (s, 3H), 3.17(m, 4H), 3.01 (m, 4H).

Example 11 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-methoxy-phenyl)-piperazine

Using 4-(4-methoxyphenyl)piperazine dihydrochloride (66.3 mg, 0.25 mmol)as an amine, the tide compound was obtained as a light brown solid (78.9mg, 60%).

MS (ISP): 529.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.52-7.57 (m,4H), 7.45-7.48 (m, 6H), 7.38 (s, 1H), 7.36 (d, 1H), 7.31 (d, 1H), 6.85(d, 2H), 6.78 (d, 2H), 3.66 (s, 3H), 3.03 (m, 8H).

Example 12 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-methoxy-phenyl)-piperazine

Using 4-(2-methoxyphenyl)piperazine (48.1 mg, 0.25 mmol) as an amine,the title compound was obtained as a light yellow solid (66.3 mg, 50%).

MS (ISP): 529.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.54-7.58 (m,4H), 7.45-7.49 (m, 6H), 7.41 (s, 1H), 7.38 (d, 1H), 7.31 (d, 1H),6.85-6.94 (m, 4H), 3.70 (s, 3H), 3.01 (m, 8H).

Example 13 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-chloro-phenyl)-piperazine

Using 4-(2-chlorophenyl)piperazine hydrochloride (58.3 mg, 0.25 mmol) asan amine, the title compound was obtained as a light yellow solid (80.4mg, 60%).

MS (ISP): 533.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.54-7.58 (m,4H), 7.45-7.49 (m, 7H), 7.43 (s, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.30(t, 1H), 7.15 (d, 1H), 7.06 (t, 1H), 3.04 (m, 8H).

Example 14 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-fluoro-phenyl)-piperazine

Using 4-(2-fluoroophenyl)piperazine (45.1 mg, 0.25 mmol) as an amine,the title compound was obtained as a light yellow solid (92.8 mg 72%).

MS (ISP): 517.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.54-7.57 (m,4H), 7.45-7.49 (m, 6H), 7.42 (s, 1H), 7.37 (d, 1H), 7.31 (d, 1H),6.96-7.17 (m, 4H), 3.05 (m, 8H).

Example 15 Preparation of 2,2-diphenyl-benzo[1,3]dioxole-5-sulfonic acidphenethyl-amide

Using phenylethylamine (30.3 mg, 0.25 mmol) as an amine, the titlecompound was obtained as a white solid (46.0 mg, 40%).

MS (ISP): 458.4 (M+H⁺, 100), 475.3 (M+NH₄₊, 45). NMR (300 MHz, DMSO-d₆)ppm: 7.44-7.56 (m, 11H), 7.33-7.21 (m, 2H), 7.10-7.21 (m, 6H), 2.95 (q,2H), 2.64 (t, 2H).

Example 16 Preparation of1-benzo[1,3]dioxol-5-yl-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine

Using 4-(3,4-dioxymethylenephenyl)piperazine hydrochloride (64.7 mg,0.25 mmol) as an amine, the title compound was obtained as a brown solid(46.6 mg, 42%).

MS (ISP): 543.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.42-7.56 (m,10H), 7.41 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 6.74 (d, 1H), 6.63 (s,1H), 6.30 (d, 1H), 5.90 (s, 2H), 3.02 (m, 8H).

Example 17 Preparation of4-benzyl-1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperidine

Using 4-benzylpiperidine (43.8 mg, 0.25 mmol) as an amine, the titlecompound was obtained as a white solid (37.6 mg, 29%).

MS (ISP): 512.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.52-7.56 (m,4H), 7.45-7.48 (m, 6H), 7.08-7.32 (m, 8H), 3.58 (m, 2H), 2.45 (m, 2H),2.19 (m, 2H), 1.58 (m, 3H), 1.15 (m, 1H).

Method B

Method B is a general method for the preparation of2,2-diphenyl-benzo[1,3]dioxole-5-sulfonamides starting from commerciallyavailable amines:

2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (93 mg, 0.25 mmol)was dissolved in pyridine (1 ml). The appropriate amine (0.25 mmol) wasadded and the reaction was heated to 60° C. overnight. Water was addedand solids respectively oils separated. The aqueous phase was decantedand the residue was stirred with acetonitrile. A solution was obtained,which was subjected to preparative reversed phase chromatography(gradient of acetonitrile/water containing 0.1% formic acid as theeluant) to yield the product after evaporation of the eluant and drying.

The following examples were prepared using the general method B:

Example 18 Preparation of2-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline

Using 1,2,3,4-tetrahydro-isoquinoline (33.3 mg, 0.25 mmol) as an amine,the title compound was obtained as a yellow solid (35 mg, 30%).

MS (ISP): 470.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.40-7.54 (m,12H), 7.24 (d, 1H), 7.05-7.13 (m, 4 H), 4.19 (s, 2H), 3.30 (t, 2H), 2.82(m, 2H).

Example 19 Preparation of 2,2-diphenyl-benzo[1,3]dioxole-5-sulfonic acidbenzyl-methyl-amide

Using N-methylbenzylamine (30.3 mg, 0.25 mmol) as an amine, the titlecompound was obtained as a yellow solid (48.3 mg, 42%).

MS (ISP): 458.4 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.43-7.58 (m,12H), 7.27-7.33 (m, 6H), 4.13 (s, 2H), 2.53 (s, 3H).

Example 20 Preparation of 2,2-diphenyl-benzo[1,3]dioxole-5-sulfonic acidbenzylamide

Using benzylamine (26.8 mg, 0.25 mmol) as an amine, the title compoundwas obtained as a light yellow solid (25.1 mg, 22%).

MS (ISN): 442.2 (M−H⁺, 100), 502.1 (M+OAc⁻, 20). NMR (300 MHz, DMSO-d₆)ppm: 8.06 (t, 1H, NH), 7.46-7.56 (m, 11H), 7.36 (d, 1H), 7.32 (s, 1H),7.14-7.18 (m, 5H), 3.97 (d, 2H).

Example 21 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-methyl-[1,4]diazepane

Using N-methylhomopiperazine (28.5 mg, 0.25 mmol) as an amine, the titlecompound was obtained as a light brown solid (23.6 mg, 21%).

MS (ISP): 451.4 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.45-7.56 (m,10H), 7.41 (s, 1H), 7.36 (d, 1H), 7.23 (s, 1H), 3.22-3.39 (m, 4H), 2.50(m, 4H, under the DMSO peak), 2.20 (s, 3H), 1.68-1.74 (m, 2H).

Example 22 Preparation of1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-[1,4]diazepane

Using 1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-homopiperazine (69.8mg, 0.25 mmol) as an amine, the title compound was obtained as a yellowsolid (76.9 mg, 52%).

MS (ISP): 616.1 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 8.38 (s, 1H),7.95 (s, 1H), 7.44-7.55 (m, 10H), 7.41 (s, 1H), 7.33 (d, 1H), 7.15 (s,1H), 3.84 (t, 2H), 3.76 (t, 2H), 3.44 (t, 2H), 3.28 (t, 2H), 1.89 (m,2H).

Example 23 Preparation of 2,2-diphenyl-benzo[1,3]dioxole-5-sulfonic acidphenylamide

Using aniline (23.3 mg, 0.25 mmol) as an amine, the title compound wasobtained as a light yellow solid (18.2 mg, 17%).

MS (ISN): 428.3 (M−H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 10.19 (s, 1H,NH), 7.43-7.52 (m, 10H), 7.32-7.35 (m, 2H), 7.14-7.21 (m, 3H), 6.98-7.09(m, 3H).

Example 24 Preparation of 2,2-diphenyl-benzo[1,3]dioxole-5-sulfonicacid[2-(4-methoxy-phenyl)-ethyl]-amide

Using 2-(4-methoxyphenyl)ethylamine (37.8 mg, 0.25 mmol) as an amine,the title compound was obtained as a light yellow solid (67.1 mg, 55%).

MS (ISN): 486.2 (M−H⁺, 100), 546.1 (M+OAc⁻, 35). NMR (300 MHz, DMSO-d₆)ppm: 7.44-7.58 (m, 11H), 7.34-7.37 (m, 2H), 7.19 (d, 1H), 7.03 (d, 2H),6.79 (d, 2H), 3.69 (s, 3H), 2.89 (q, 2H), 2.58 (t, 2H).

Example 25 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-methyl-piperazine

Using N-methylpiperazine (25.0 mg, 0.25 mmol) as an amine, the titlecompound was obtained as a white solid (11 mg, 10%).

MS (ISP): 437.4 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.53-7.57 (m,4H), 7.45-7.49 (m, 6H), 7.36 (s, 1H), 7.32 (d, 1H), 7.29 (d, 1H), 2.87(m, 4H), 2.33 (m, 4H), 2.11 (s, 3H).

Example 26 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine

4-(4-Fluorophenyl)-1,2,3,4-tetrahydropyridine hydrochloride (2.56 g, 12mmol) was suspended in methylene chloride (150 ml).Ethyldiisopropylamine (4.2 ml, 25 mmol) was added and the solution wasstirred for 10 minutes at room temperature.2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (3.72 g, 10 mmol) wasadded and the reaction was stirred at room temperature for 2 hours. Thesolvent was evaporated and the residue was purified by columnchromatography on silical gel (100 g, dichloromethane eluant). Theproduct was stirred with n-hexane, filtered and dried to yield thesulfonamide as white crystals (3.86 g, 75%).

MS (ISP): 514.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.50-7.54 (m,4H), 7.44-7.48 (m, 7H), 7.36-7.40 (m, 3H), 7.26 (d, 1H), 7.09 (t, 2H),6.03 (m, 1H), 3.68 (m, 2H), 3.23 (t, 2H), 2.50 (s, 2H, under DMSO peak).

Example 27 Preparation of4-(4-chloro-phenyl)-1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-1,2,3,6-tetrahydro-pyridine

4-(4-Chlorophenyl)-1,2,3,4-tetrahydropyridine hydrochloride (19.37 mg,0.10 mmol) was suspended in methylene chloride (2 ml).Ethyldiisopropylamine (0.035 ml, 0.20 mmol) was added and the solutionwas shaken for 10 minutes at room temperature.2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (37.28 mg, 0.10 mmol)was added and the reaction was shaken at room temperature for 12 hours.Aqueous HCl (0.1 N, 1.0 ml) was added and the mixture shaken for 30minutes, the aqueous layer removed and the organic phase concentratedand purified by preparative reverse phase HPLC (YMC, ODS-AQ packing;20%→95% CH₃CN/H₂O) to yield the sulfonamide (2.6 mg, 5%).

MS (ISP): 530.2 (M+H⁺, 100). NMR (500 MHz, DMSO-d₆) ppm: 7.31-7.56 (m,16H), 7.26 (d, 1H), 6.10 (m, 1H), 3.70 (m, 2H), 3.24 (m, 2H), 2.50 (m,2H, under DMSO peak).

Example 28 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-phenyl-1,2,3,6-tetrahydro-pyridine

4-Phenyl-1,2,3,4-tetrahydropyridine hydrochloride (15.92 mg, 0.10 mmol)was suspended in methylene chloride (2 ml). Ethyldiisopropylamine (0.035ml, 0.20 mmol) was added and the solution was shaken for 10 minutes atroom temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride(37.28 mg, 0.10 mmol) was added and the reaction was shaken at roomtemperature for 12 hours. Aqueous HCl (0.1 N, 1.0 ml) was added and themixture shaken for 30 minutes, the aqueous layer removed and the organicphase concentrated and purified by preparative reverse phase HPLC (YMC,ODS-AQ packing; 20%→95% CH₃CN/H₂O) to yield the sulfonamide (23.6 mg,48%).

MS (ISP): 596.2 (M+H⁺, 100). NMR (500 MHz, DMSO-d₆) ppm: 7.22-7.55 (m,17H), 6.06 (m, 1H), 3.70 (m, 2H), 3.24 (m, 2H), 2.50 (m, 2H, under DMSOpeak).

Example 29 Preparation of racemic1-[2-(2-chloro-phenyl)-2-(4-methoxy-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Method C

4-(Piperidine-l-sulfonyl)-benzene-1,2-diol (60 mg, 0.2 mmol) and(4-methoxyphenyl)-(2-chlorophenyl)-dichloromethane (51 mg, 0.2 mmol) wasrefluxed overnight in toluene (2 ml). After cooling the reaction to roomtemperature the solvent was evaporated. The residue was dissolved inmethylene chloride and purified by column chromatography (methylenechloride eluant) on silica gel to afford the product as a colorlesssolid (42 mg, 39%).

MS (ISP): 486.3 (M+H⁺, 100). NMR (300 MHz, CDCl₃) ppm: 7.80-7.90 (m,1H), 7.30-7.43 (m, 8H), 6.97 (d, 1H), 6.89 (d, 1H), 3.82 (s, 3H), 2.98(m, 4H), 1.60-1.70 (m, 4H), 1.40-1.50 (m, 2H).

The following examples were prepared following method C:

Example 30 Preparation of racemic1-[2-(2-chloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 4-fluorophenyl-2-chlorophenyl-dichloromethane (57 mg, 0.2 mmol) asa starting material, the title compound was obtained as a colorless foam(68 mg, 71%). Column chromatography was performed on silica gel (25 g,methylene chloride eluant).

MS (ISP): 474.2 (M+H⁺, 100). NMR (300 MHz, CDCl₃) ppm: 7.84 (m, 1H),7.32-7.47 (m, 6H), 7.27 (d, 1H), 7.08 (t, 2H), 6.99 (d, 1H), 2.95-3.01(m, 4H), 1.60-1.68 (m, 4H), 1.42-1.47 (m, 2H).

Example 31 Preparation of racemic1-[2-(2-chloro-phenyl)-2-p-tolyl-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 4-methylphenyl-2-chlorophenyl-dichloromethane (57 mg, 0.2 mmol) asa starting material, the title compound was obtained as a light yellowfoam (46 mg, 44%). Column chromatography was performed on silica gel (25g, methylene chloride eluant).

MS (ISP): 470.2 (M+H⁺, 100). NMR (300 MHz, CDCl₃) ppm: 7.83 (m, 1H),7.31-7.42 (m, 7H), 7.20 (d, 2H), 6.97 (d, 1H), 2.96-3.02 (m, 4H),1.60-1.68 (m, 4H), 1.42-1.46 (m, 2H).

Example 32 Preparation of racemic1-[2-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 4-methoxphenyl-4-chlorophenyl-dichloromethane (60 mg, 0.2 mmol) asa starting material, the title compound was obtained as a light redsolid (35 mg, 36%). Column chromatography was performed on silica gel(25 g, methylene chloride eluant).

MS (EI): 485.2 (M⁺, 65), 374.2 ([M−PhCl]⁺, 100). NMR (300 MHz, CDCl₃)ppm: 7.49 (d, 2H), 7.42 (d, 2H), 7.32 (d, 2H), 7.22 (s, 1H), 6.94 (d,1H), 6.90 (d, 2H), 2.95-2.99 (m, 4H), 1.60-1.68 (m, 4H), 1.40-1.44 (m,2H).

Example 33 Preparation of racemic1-[2-(4-chloro-phenyl)-2-p-tolyl-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 4-methylphenyl-4-chlorophenyl-dichloromethane (85 mg, 0.3 mmol) asa starting material, the title compound was obtained as a colorless foam(138 mg, 97%). Column chromatography was performed on silica gel (25 g,4/1 hexane/ethyl acetate eluant).

MS (ISP): 470.2 (M⁺, 100). NMR (300 MHz, CDCl₃) ppm: 7.49 (d, 2H), 7.40(d, 2H), 7.36 (d, 2H), 7.31 (d, 1H), 7.23 (d, 1H), 6.94 (d, 2H),2.95-2.99 (m, 4H), 1.60-1.68 (m, 4H), 1.39-1.46 (m, 2H).

Example 34 Preparation of1-[2,2-bis-(4-chloro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using bis-(4-chlorophenyl)-dichloromethane (61 mg, 0.2 mmol) as astarting material, the title compound was obtained as a colorless solid(77 mg, 78%). Column chromatography was performed on silica gel (25 g,methylene chloride eluant).

MS (EI): 489.1 (M⁺, 30), 378.1 ([M−PhCl]⁺, 30), 231.1 (70), 84.3 (100).NMR (300 MHz, CDCl₃) ppm: 7.47 (d, 4H), 7.37 (d, 4H), 7.33 (d, 1H), 7.25(s, 1H), 6.96 (d, 1H), 2.95-3.00 (m, 4H), 1.60-1.68 (m, 4H), 1.40-1.46(m, 2H).

Example 35 Preparation of racemic1-[2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 4-fluorophenyl-phenyl-dichloromethane (51 mg, 0.2 mmol) as astarting material, the title compound was obtained as a whitecrystalline solid (66 mg, 75%) after stirring the crude product indiethyl ether, filtration and drying. m.p.: 125-126° C.

Example 36 Preparation of racemic1-[2-(4-methoxy-phenyl)-2-phenyl-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 4-methoxyphenyl-phenyl-dichloromethane (53 mg, 0.2 mmol) as astarting material, the title compound was obtained as a white solid (56mg, 62%). Column chromatography was performed on silica gel (25 g, 4/1hexane/ethyl acetate).

MS (ISP): 452.4 (M⁺, 100). NMR (300 MHz, CDCl₃) ppm: 7.41-7.54 (m, 7H),7.33 (s, 1H), 7.31 (d, 4H), 7.23 (d, 1H), 7.00 (d, 2H), 3.76 (s, 3H),2.87 (m, 4H), 1.53 (m, 4H), 1.35 (m, 2H).

Example 37 Preparation of racemic1-[2-(4-chloro-phenyl)-2-p-tolyl-benzo[1,3]dioxole-5-sulfonyl]-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine

Using 4-chlorophenyl-4-methylphenyl-dichloromethane (57 mg, 0.2 mmol)and4-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-benzene-1,2-diol(69 mg, 0.2 mmol) as a starting material, the title compound wasobtained as an off-white crystalline solid (90 mg, 80%) after taking theresidue up in hexane/ethyl acetate (4/1), stirring for 10 minutes,filtering the solid and drying.

MS (EI): 561.2 (M⁺, 10), 176.2 (100), 149.2 (50). NMR (300 MHz, CDCl₃)ppm: 7.47 (d, 2H), 7.18-7.40 (m, 9H), 6.99 (d, 2H), 6.96 (d, 2H), 5.89(m, 1H), 3.75 (m, 2H), 3.32 (t, 2H), 2.57 (m, 2H), 2.36 (s, 3H).

Preparation of4-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-benzene-1,2-diol

1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine(3.2 g, 6.2 mmol) was dissolved in methylene chloride (100 ml).Trifluoroacetic acid (50 ml) was added dropwise and the reaction wasstirred for 5 hours at room temperature. The solvent was evaporated andthe residue was purified by column chromatography on silica gel (100 g,methylene chloride then ethyl acetate as eluant). The product wascrystallized from ether/hexane to give a white solid (2.1 g, 96%).

MS (ISN): 348.2 (M−H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 10.0 (br s, 1H,OH), 9.80 (br s, 1H, OH), 7.44 (d, 1H), 7.42 (d, 1H), 7.08-7.19 (m, 4H),6.92 (d, 1H), 6.07 (brs, 1H), 3.59 (br s, 2H), 3.13 (m, 2H), 2.51 (m,2H, under DMSO peak).

Example 38 Preparation of racemic1-[2-(4-chloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 4-chlorophenyl-4-fluorophenyl-dichloromethane (57 mg, 0.2 mmol) asa starting material, the title compound was obtained as a colorless foam(77 mg, 81%). Column chromatography was performed on silica gel (25 g,4/1 hexane/ethyl acetate eluant).

MS (EI): 473.2 (M⁺, 30), 215.2 (40), 84.3 (100). NMR (300 MHz, CDCl₃)ppm: 7.46-7.53 (m, 4H), 7.32-7.39 (m, 3H), 7.24 (s, 1H), 7.09 (t, 2H),6.96 (d, 1H), 2.96-3.00 (m, 4H), 1.60-1.68 (m, 4H), 1.40-1.46 (m, 2H).

Example 39 Preparation of racemic1-[2-(2,4-dichloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 2,4-dichlorophenyl-4-fluorophenyl-dichloromethane (65 mg, 0.2mmol) as a starting material, the title compound was obtained as acolorless foam (81 mg, 80%). Column chromatography was performed onsilica gel (25 g, 4/1 hexane/ethyl acetate eluant).

MS (ISP): 508.2 (M+HF⁺, 100). NMR (300 MHz, CDCl₃) ppm: 7.78 (d, 1H),7.32-7.47 (m, 3H), 7.32-7.37 (m, 2H), 7.28 (s, 1H), 7.08 (t, 2H), 6.99(d, 1H), 2.97-3.00 (m, 4H), 1.61-1.68 (m, 4H), 1.40-1.47 (m, 2H).

Example 40 Preparation of1-[2,2-Bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using bis-(4-fluorophenyl)-dichloromethane (55 mg, 0.2 mmol) as astarting material, the title compound was obtained as a colorless foam(75 mg, 82%). Column chromatography was performed on silica gel (25 g,4/1 hexane/ethyl acetate eluant). m.p.: 148-149° C.

Example 41 Preparation of racemic1-[2-(3-chloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 3-chlorophenyl-4-fluorphenyl-dichloromethane (58 mg, 0.2 mmol) asa starting material, the title compound was obtained as a colorlessviscous oil (82 mg, 86%). Column chromatography was performed on silicagel (25 g, 4/1 hexane/ethyl acetate eluant).

MS (ISP): 474.2 (M+H⁺, 100). NMR (300 MHz, CDCl₃) ppm: 7.49-7.55 (m,3H), 7.33-7.44 (m, 4H), 7.26 (s, 1H), 7.09 (t, 2H), 6.97 (d, 1H),2.96-3.00 (m, 4H), 1.60-1.68 (m, 4H), 1.40-1.46 (m, 2H).

Example 42 Preparation of racemic1-[2-(4-chloro-phenyl)-2-(2-chloro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Using 2-chlorophenyl-4-chlorophenyl-dichloromethane (61 mg, 0.2 mmol) asa starting material, the title compound was obtained as a colorlesssolid (40 mg, 41%). Column chromatography was performed on silica gel(25 g, Dichloromethane eluant).

MS (EI): 489.1 (M⁺, 30), 378.1 (35), 231.1 (60), 84.2 (100). NMR (300MHz, CDCl₃) ppm: 7.42-7.86 (m, 1H), 7.33-7.44 (m, 8H), 7.27 (d, 1H),6.99 (d, 1H), 2.96-3.00 (m, 4H), 1.60-1.68 (m, 4H), 1.42-1.47 (m, 2H).

Method D

The bisaryl-dichloromethane derivatives needed for the preparation ofthe above described examples were prepared according to the followingmethod D following a literature procedure (R. K. Ramchandani, R. D.Wakharkar, A. Sudalai, Tetrahedron Lett. 37 (23) (1996) 4063-4064).

Preparation of (4-methoxyphenyl)(2-chlorophenyl)-dichloromethane

Aluminium trichloride (400 mg, 3 mmol) is suspended in1,2-dichloroethane (1.4 ml). At 0° C. under argon2-chlorobenzotrifluoride (180 mg, 1 mmol) is added. A deep red solutionis obtained to which anisole (108 mg, 1 mmol) is added. The reaction wasstirred at 0° C. for 3 hours. It was poured onto ice, stirred for 5minutes and extracted twice with methylene chloride. The combinedorganic layers were washed with brine, dried over sodium sulfate andfiltered. The solvent was evaporated to leave the product as dark redviscous oil (416 mg 138%), which was used without purification in thenext step.

Known bisaryl-dichloromethanes prepared by this method:

-   4-Methylphenyl-4-chlorophenyl-dichloromethane-   Bis-(4-chlorophenyl)-dichloromethane-   Chlorophenyl-4-chlorophenyl-dichloromethane-   (4-Methoxyphenyl) (2-chlorophenyl)-dichloromethane

The following bisaryl-dichlormethane derivatives are unknown inliterature and are prepared according to method D from commerciallyavailable starting materials. The compounds were not purified, becausesome of them are unstable on column chromatography, but were usedinstead without Purification as crude products in the next step:

Preparation of 4-fluorophenyl-2-chlorophenyl-dichloromethane

From 2-chlorobenzotrifluoride (180 mg, 1 mmol), AlC₃ (400 mg, 3 mmol)and fluorobenzene (96 mg, 1 mmol), light yellow oil (380 mg, 131%crude).

Preparation of 4-methylphenyl-2-chlorophenyl-dichloromethane

From 2-chlorobenzotrifluoride (180 mg, 1 mmol), AlCl₃ (400 mg, 3 mmol)and toluene (92 mg, 1 mmol), light yellow oil (345 mg, 120% crude).

Preparation of 4-methoxyphenyl-4-chlorophenyl-dichloromethane

From 4-chlorobenzotrifluoride (180 mg, 1 mmol), AlCl₃ (400 mg, 3 mmol)and anisole (108 mg, 1 mmol), red solid (345 mg, 120% crude), containsthe benzophenone (ca 30%).

Preparation of 4-chlorophenyl-4-fluorophenyl-dichloromethane

From 4-chlorobenzotrifluoride (180 mg, 1 mmol), AlCl₃ (400 mg, 3 mmol)and fluorobenzene (96 mg, 1 mmol), light yellow oil (382 mg, 131%crude).

Preparation of 2,4-dichlorophenyl-4-fluorophenyl-dichloromethane

From 2,4-dichlorobenzotrifluoride (215 mg, 1 mmol), AlCl₃ (400 mg, 3mmol) and fluorobenzene (96 mg, 1 mmol), light yellow oil (382 mg, 118%crude).

Preparation of 3-chlorophenyl-4-fluorophenyl-dichloromethane

From 3-chlorobenzotrifluoride (180 mg, 1 mmol), AlCl₃ (400 mg, 3 mmol)and fluorobenzene (96 mg, 1 mmol), light yellow oil (384 mg, 132%crude).

Preparation of 4-fluorophenyl-phenyl-dichloromethane

From benzotrifluoride (146 mg, 1 mmol), AlCl₃ (400 mg, 3 mmol) andfluorobenzene (96 mg, 1 mmol), light yellow oil (335 mg, 131% crude).

The following bisaryl-dichloromethanes are known in the literature buttheir synthesis is not described. These compounds were prepared withmethod D:

Preparation of bis-(4-fluorophenyl)-dichloromethane (EP96008)

From 4-fluorobenzotrifluoride (164 mg, 1 mmol), AlCl₃ (400 mg, 3 mmol)and fluorobenzene (96 mg, 1 mmol), light yellow oil (377 mg, 138%crude). Preparation of 4-methoxyphenyl-phenyl-dichloromethane (R.Laatikainen, V. Kral, J. Chem. Soc., Perkin Trans. 2 (8) (1985)1091-1100; U.S. Pat. No. 3,824,310):

From benzotrifluoride (146 mg, 1 mmol), AlCl₃ (400 mg, 3 mmol) andanisole (108 mg, 1 mmol), dark red viscous oil (352 mg, 132% crude).

Preparation of 4-(piperidine-1-sulfonyl)-benzene-1,2-diol

1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperidine (1.92 g, 4.5mmol) was dissolved in methylene chloride (69 ml). At room temperaturetrifluoroacetic acid (20.7 ml) and water (8 drops) were added. Thereaction was stirred at room temperature for 24 hours. The solvent wasevaporated and the residue was taken up in n-pentane three times andevaporated again in order to remove trifluoroacetic acid. The residuewas purified by column chromatography on silica gel (100 g, methylenechloride then 1/19 methanol/methylene chloride eluant). The product wasprecipitated from diethyl ether/n-pentane. The solvent was evaporatedand the residue was stirred with n-pentane. The solid was filtered anddried to yield the product as a white crystalline solid (1.13 g, 97%).

MS (ISN): 256.0 (M−H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 9.98(s, 1H,OH), 9.69 (s, 1H, OH), 7.05 (dd, 1H), 7.01 (dd, 1H), 6.90 (d, 1H),2.78-2.83 (m, 4H), 1.50-1.68 (m, 4H), 1.30-1.40 (m, 2H).

Method E

2,2-Diphenyl-benzo[1,3]dioxole-5-carboxylic acidbenzotriazol-1-yl ester(87 mg, 0.2 mmol), the appropriate amine (22 mg, 0.25 mmol) andethyldiisopropylamine (32 mg, 0.25 mmol) were dissolved in acetonitrile(2 ml) and stirred at room temperature for 3 hours. Water (20 ml) wasadded and the reaction was stirred at room temperature for 1 hour. Theprecipitate was filtered off, washed with water and dried in high vacuumto yield the product as a crystalline white solid.

The preparation of the activated ester,2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester, is described in the literature (EP544166).

The following examples were prepared following method E:

Example 43 Preparation of racemic(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(3-hydroxy-pyrrolidin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol) and 3-pyrrolidinol (22 mg, 0.25 mmol), the titlecompound was obtained as a white crystalline solid (73 mg, 94%). m.p.:106-107° C.

Example 44 Preparation of4-(2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl)-piperazine-1-carbaldehyde

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol) and formyl-piperazine (32 mg, 90% pure, 0.25mmol), the title compound was obtained as a white crystalline solid (73mg, 88%). m.p. 176-177° C.

Example 45 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-hydroxymethyl-piperidin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol) and 4-(hydroxymethyl)-piperidine (29 mg, 0.25mmol), the title compound was obtained as a white crystalline solid (76mg, 91%). m.p. 197-198° C.

Example 46 Preparation of(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol) and 1,4-dioxa-8-azaspiro(4,5)decan (36 mg, 0.25mmol), the title compound was obtained as a white crystalline solid (74mg, 83%). m.p. 150-151° C.

Example 47 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol) and morpholine (22 mg, 0.25 mmol), the titlecompound was obtained as a white crystalline solid (64 mg, 82%). m.p.149-150° C.

Example 48 Preparation(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol) and 1-methylpiperazine (25 mg, 0.25 mmol), thetitle compound was obtained as a white crystalline solid (72 mg, 90%).m.p. 115-116° C.

Example 49 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-isopropyl-piperazin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol) and 1-(2-propyl)-piperazine (32 mg, 0.25 mmol),the title compound was obtained as a colorless foam (84 mg, 98%). Workup: after addition of water (20 ml), the reaction was stirred for 1 hourat room temperature. Methylene chloride was added and the mixture wasstirred 10 minutes. The organic layer was separated, washed with waterand dried over sodium sulfate. The solvent was evaporated to yield theproduct after drying in high vacuum.

MS (ISP): 429.6 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.51-7.56 (m,4H), 7.43-7.47 (m, 6H), 7.08 (d, 1H), 7.07 (s, 1H), 6.92 (d, 1H),3.3-3.6 (br m, 4H), 2.65 (sept, 1H), 2.38-2.42 (br m, 4H), 0.95 (d, 6H).

Example 50 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl)-piperidin-4-one

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 4-piperidone monohydrate hydrochloride (39 mg,0.25 mmol) and ethyl-diisopropylamine (58 mg, 0.45 mmol), the titlecompound was obtained as a light yellow foam (75 mg, 94%). Work up:after addition of water (20 ml), the reaction was stirred for 1 hour atroom temperature. Methylene chloride was added and the mixture wasstirred 10 minutes. The organic layer was separated, washed with waterand dried over sodium sulfate. The solvent was evaporated to yield theproduct after drying in high vacuum.

MS (ISP): 400.5 (M+H⁺, 100), 417.3 (M+NH₄ ⁺, 40), 799.3 (2M+H⁺, 20). NMR(300 MHz, DMSO-D₆) ppm: 7.47-7.57 (m, 4H), 7.44-7.47 (m, 6H), 7.17 (s,1H), 7.11 (d, 1H), 7.05 (d, 1H), 3.62-3.82 (br m, 4H), 2.39-2.44 (br m,4H).

Example 51 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-hydroxy-piperidin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 4-hydroxypiperidine hydrochloride (34 mg, 0.25mmol) and ethyl-diisopropylamine (58 mg, 0.45 mmol), the title compoundwas obtained as a colorless foam (73 mg, 91%). Work up: after additionof water (20 ml), the reaction was stirred for 1 hour at roomtemperature. Methylene chloride was added and the mixture was stirred 10minutes. The organic layer was separated, washed with water and driedover sodium sulfate. The solvent was evaporated to yield the productafter drying at high vacuum.

MS (ISP): 402.5 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.51-7.56 (m,4H), 7.43-7.49 (m, 6H), 7.07 (d, 1H), 7.05 (s, 1H), 6.91 (d, 1H), 4,76(d, 1H, OH), 3.70 (m, 1H), 3.11-3.18 (m, 2H), 2.51 (m, 2H under the DMSOpeak), 1.63-1.79 (m, 2H), 1.25-1.39 (m, 2H).

Example 52 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-pyrrolidin-1-yl-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), pyrrolidin (18 mg, 0.25 mmol) andethyl-diisopropylamine (32 mg, 0.25 mmol), the title compound wasobtained as a light yellow foam (75 mg, 91%). Work up: after addition ofwater (20 ml), the reaction was stirred for 1 hour at room temperature.Methylene chloride was added and the mixture was stirred 10 minutes. Theorganic layer was separated, washed with water and dried over sodiumsulfate. The solvent was evaporated to yield the product after dryingunder high vacuum.

MS (ISP): 372.3 (M+H⁺, 100), 743.3 (2M+H⁺, 80). NMR (300 MHz, DMSO-D₆)ppm: 7.48-7.56 (m, 4H), 7.43-7.48 (m, 6H), 7.18 (s, 1H), 7.09 (d, 1H),7.05 (d, 1H), 3.35-3.42 (m, 4H), 1.77-1.84 (m, 4H).

Example 53 Preparation of racemic1-(2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl)-piperidine-3-carboxylicacid ethyl ester

Method F

2,2-Diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-yl ester(87 mg, 0.2 mmol), (rac)-ethyl nipecotate (36 mg, 0.25 mmol) andethyl-diisopropylamine (32 mg, 0.25 mmol) were dissolved in acetonitrile(1 ml) and stirred at room temperature over night. The reaction mixturewas purified by preparative HPLC (acetonitrile/water 0.1% formic acid asgradient) to yield the product as a white solid (24.8 mg, 27%).

MS (ISP): 458.4 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.52-7.56 (m,4H), 7.43-7.46 (m, 6H), 7.08 (d, 1H), 7.07 (s, 1H), 6.92 (d, 1H), 4.03(m, 2H), 3.12 (m, 2H), 2.50 (m, 2H, under DMSO peak), 1.92 (m, 1H), 1.63(m, 2H), 1.43 (m, 2H), 1.12 (m, 3H).

The following examples were prepared according to the above describedmethod F:

Example 54 Preparationof[4-(5-chloro-2-methoxy-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 1-(5-chloro-2-methoxy-phenyl)piperazinehydrochloride (66 mg, 0.25 mmol) and ethyl-diisopropylamine (64 mg, 0.50mmol), the title compound was obtained as a white solid (42.7 mg, 41%).

MS (ISP): 527.1 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.44-7.60 (m,10H), 6.87-7.01 (m, 6H), 3.78 (s, 3H), 3.06 (br m, 4H), 2.97 (br m, 4H).

Example 55 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-m-tolyl-piperazin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 1-(3-tolyl)piperazine dihydrochloride (62 mg,0.25 mmol) and ethyl-diisopropylamine (96 mg, 0.75 mmol), the titlecompound was obtained as a light yellow solid (14.0 mg, 15%).

MS (ISP): 477.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.53-7.57 (m,4H), 7.44-7.48 (m, 6H), 7.09-7.13 (m, 3H), 6.99 (d, 1H), 6.75 (m, 2H),6.62 (d, 1H), 3.60 (br m, 4H), 3.12 (br m, 4H), 2.24 (s, 3H).

Example 56 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-methanone

Method G

2,2-Diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-yl ester(217 mg, 0.5 mmol), piperidine (46 mg, 0.55 mmol) andethyl-diisopropylamine (0.1 ml, 0.6 mmol) were dissolved in methylenechloride (10 ml). The solution was stirred at room temperature for 4hours and the solvent was evaporated. The residue was purified by columnchromatography on silica gel (20 g, ethyl acetate eluant) to yield theproduct as a white solid (135 mg, 70%).

MS (ISP): 386.4 (M+H⁺, 100), 771.3 (2M+H⁺, 25). NMR (300 MHz, DMSO-d₆)ppm: 7.52-7.56 (m, 4H), 7.43-7.48 (m, 6H), 7.07 (d, 1H), 7.04 (s, 1H),6.90 (d, 1H), 3.40 (br m, 2H), 1.58 (br m, 2H), 1.48 (br m, 6H).

The following examples were prepared according to method G:

Example 57 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-o-tolyl-piperazin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 1-(2-tolyl)piperazine dihydrochloride (62 mg,0.25 mmol) and ethyl-diisopropylamine (96 mg, 0.75 mmol), the titlecompound was obtained as a light yellow solid (1.1 mg, 1%).

MS (ISP): 477.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.53-7.57 (m,4H), 7.44-7.47 (m, 6H), 7.09-7.14 (m, 4H), 6.91-7.03 (m, 3H), 3.61 (brm, 4H), 2.82 (br m, 4H), 2.26 (s, 3H).

Example 58 Preparation of racemic1-(2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl)-piperidine-2-carboxylicacid ethyl ester

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), racemic ethyl pipecolinate (39 mg, 0.25 mmol)and ethyl-diisopropylamine (32 mg, 0.25 mmol), the title compound wasobtained as a white solid (22.6 mg, 24%).

MS (ISP): 458.4 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.53-7.56 (m,4H), 7.43-7.49 (m, 6H), 7.09 (d, 1H), 7.02 (s, 1H), 6.92 (d, 1H), 5.14(br m, 1H), 4.16 (br q, 2H), 3.58 (br m, 1H), 3.12 (br m, 1H), 2.11 (brm, 1 h), 1.18-1.63 (m, 9 H).

Example 59 Preparation of[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 1-(2,3-dichlorophenyl)piperazine hydrochloride(66.9 mg, 0.25 mmol) and ethyl-diisopropylamine (64 mg, 0.50 mmol), thetitle compound was obtained as a light yellow solid (58.3 mg, 55%).

MS (ISP): 531.1 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.53-7.57 (m,4H), 7.44-7.48 (m, 6H), 7.31-7.33 (m, 2H), 7.11-7.14 (m, 2H), 7.09 (d,1H), 7.02 (d, 1H), 3.63 (br m, 4H), 2.98 (br m, 4H).

Example 60 Preparation of[4-(4-chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 1-(4-chloro-3-trifluoromethyl-phenyl)piperazine(66.2 mg, 0.25 mmol) and ethyl-diisopropylamine (32 mg, 0.25 mmol), thetitle compound was obtained as a white solid (35.8 mg, 30%).

MS (ISP): 565.2 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.52-7.58 (m,4H), 7.44-7.49 (m, 7H), 7.27 (s, 1H), 7.23 (d, 1H), 7.13 (s, 1H), 7.10(d, 1H), 7.00 (d, 1H), 3.60 (br m, 4H), 3.28 (br m, 4H).

Example 61 Preparation of racemic(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(3-hydroxymethyl-piperidin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), racemic 3-hydroxymethylpiperidine (28.8 mg,0.25 mmol) and ethyl-diisopropylamine (32 mg, 0.25 mmol), the titlecompound was obtained as a white solid (6.0 mg, 7%).

MS (ISP): 416.4 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 7.52-7.58 (m,4H), 7.43-7.46 (m, 6H), 7.06 (d, 1H), 7.05 (s, 1H), 6.91 (d, 1H), 4.50(br s, 1H. OH), 3.32 (m, 2H), 2.45 (m, 2H), 1.10-1.78 (m, 7H).

Example 62 Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 1-(2-pyrazinyl)piperazine (41.1 mg, 0.25 mmol)and ethyl-diisopropylamine (32 mg, 0.25 mmol), the title compound wasobtained as a white solid (19.0 mg, 20%).

MS (ISP): 465.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 8.31 (s, 1H),8.13 (s, 1H), 7.86 (s, 1H), 7.53-7.57 (m, 4H), 7.44-7.48 (m, 6H), 7.14(s, 1H), 7.11 (d, 1H), 7.01 (d, 1H), 3.61 (br m, 8H).

Example 63 Preparation of(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone

From 2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-ylester (87 mg, 0.2 mmol), 1-(2-pyridyl)piperazine (40.8 mg, 0.25 mmol)and ethyl-diisopropylamine (32 mg, 0.25 mmol), the title compound wasobtained as a white solid (53.2 mg, 57%).

MS (ISP): 464.3 (M+H⁺, 100). NMR (300 MHz, DMSO-d₆) ppm: 8.11 (m, 1H),7.52-7.57 (m, 4H), 7.44-7.48 (m, 7H), 7.13 (s, 1H), 7.10 (d, 1H), 7.00(d, 1H), 6.82 (d, 1H), 6.64 (dd, 1H), 3.53 (br m, 8H).

Example 64 Preparation of(4-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone

Method H

4-Fluoro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (336 mg, 1mmol) was dissolved in dichloromethane (15 ml). EDCI (210 mg, 1.1 mmol)and 1-methyl-piperazine (220 mg, 2.2 mmol) were added and the solutionwas stirred for 5 hours at room temperature. The reaction wasconcentrated and the residue was purified by column chromatography onsilica gel (20 g, 5% methanol in dichloromethane eluant) to yield theproduct as white crystals (150 mg, 37%).

MS (ISP): 419.4 (M+H⁺, 100), 460.5 (M+MeCN+H⁺, 70), 837.4 (2M+H⁺, 50).NMR (300 MHz, DMSO-D₆) ppm: 7.52-7.58 (m, 4H), 7.46-7.50 (m, 6H), 7.01(d, 1H), 6.92 (d, 1H), 3.60 (m, 2H), 3.22 (m, 2H), 2.32 (m, 2H), 2.22(m, 2H), 2.18 (s, 3H).

Preparation of 4-fluoro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid

4-Fluoro-2,2-diphenyl-benzo[1,3]dioxole (5.8 g, 20 mmol) were dissolvedin THF (40 ml). The reaction was cooled to −78° C. under argon. TMEDA(2.9 ml, 20 mmol) was added followed by n-butyl lithium (12.5 ml, 1.6 Nin hexane) dropwise. The reaction was stirred at −78° C. for 2 hours.Carbon dioxide (20 g) was added at that temperature. The reaction wasallowed to warm to 0° C. and poured into water (80 ml). The reaction wasextracted twice with ethyl acetate. The aqueous layer was neutralizedwith 1N aqueous HCl solution, extracted twice with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate andfiltered. The solvent was evaporated and the residue suspended inn-hexane, stirred for 10 minutes and the product was filtered off toyield the acid as a white solid (4.0 g, 60%). m.p.: 189-191° C.

Preparation of 4-fluoro-2,2-diphenyl-benzo[1,3]dioxole

3-Fluorocatechol (12.81 g, 100 mmol) and dichlorodiphenylmethane (23.71g, 100 mol) were dissolved in toluene (250 ml) and heated at refluxovernight. The solvent was evaporated and the residue waschromatographied on silica gel (200 g, 1/1 Dichloromethane/n-hexaneeluant) to yield the ketal as a white crystalline solid (26.74 g, 91%).m.p.: 65-67° C.

The following examples were prepared using the method H:

Example 65 Preparation of(4-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

From 4-fluoro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (336 mg,1 mmol), EDCI (210 mg, 1.1. mmol) and morpholine (190 mg, 2.2 mmol), thetitle compound was obtained as a white solid (183 mg, 46%).Chromatography was performed on silica gel (20 g, 5% methanol indichloromethane eluant).

MS (ISP): 406.4 (M+H⁺, 100), 811.2 (2M+H⁺, 25). NMR (300 MHz, DMSO-D₆)ppm: 7.54-7.58 (m, 4H), 7.46-7.50 (m, 6H), 7.01 (d, 1H), 6.96 (d, 1H),3.63 (m, 4H), 3.52 (m, 2H), 3.27 (m, 2H).

Example 66 Preparation of(4-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

From 4-fluoro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (336 mg,1 mmol), EDCI (210 mg, 1.1. mmol) and piperidine (187 mg, 2.2 mmol), thetitle compound was obtained as a white solid (103 mg, 26%).Chromatography was performed on silica gel (20 g, 5% methanol indichloromethane eluant).

MS (ISP): 404.5 (M+H⁺, 100), 807.4 (2M+H⁺, 30). NMR (300 MHz, DMSO-D₆)ppm: 7.48-7.56 (m, 4H), 7.42-7.48 (m, 6H), 6.98 (d, 1H), 6.89 (d, 1H),3.58 (m, 2H), 3.20 (m, 2H), 1.46-1.62 (m, 4H), 1.38-1.46 (m, 2H).

Example 67 Preparation of(4,7-dichloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

From 4,7-dichloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (154mg, 0.4 mmol), EDCI (84 mg, 0.44 mmol) and piperidine (75 mg, 0.88mmol), the title compound was obtained as a white solid (27 mg, 15%).Chromatography was performed on silica gel (20 g, ethyl acetate eluant).

MS (ISP): 454.4 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.48-7.55 (m,1OH), 7.09 (s, 1H), 3.58 (m, 2H), 3.14 (m, 2H), 1.48-1.60 (m, 4H),1.38-1.48 (m, 2H).

Preparation of 4,7-dichloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylicacid

2,5-Dichloro-3,4-dihydroxybenzoic acid (1 g, 4.48 mmol) anddichlorodiphenylmethane (2.12 g, 9.96 mmol) are dissolved in toluene (40ml) and heated to reflux for 24 hours. After cooling the solvent isevaporated and the residue is purified by column chromatography on silicagel (100 g, dichloromethane then 5% methanol in dichloromethane eluant)to yield the acid as white crystals (490 mg, 28%).

MS (ISN): 385.0 (M−H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 13.47 (br s,1H, OH), 7.59 (s, 1H), 7.54 (br m, 10 H).

The preparation of 2,5-dichloro-3,4-dihydroxybenzoic acid is describedin the literature (EP416410).

Example 68 Preparation of(4,7-dichloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

From 4,7-dichloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (154mg, 0.4 mmol), EDCI (84 mg, 0.44 mmol) and morpholine (77 mg, 0.88mmol), the title compound was obtained as a white solid (88 mg, 49%).Chromatography was performed on silica gel (20 g, ethyl acetate eluant).

MS (ISP): 456.4 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.52 (m, 10H),7.15 (s, 1H), 3.45-3.72 (m, 6H), 3.20 (m, 2H).

Example 69 Preparation of(4,7-dichloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone

From 4,7-dichloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (115mg, 0.3 mmol), EDCI (63 mg, 0.33 mmol) and N-methylpiperazine (66 mg,0.66 mmol), the title compound was obtained as a white solid (28 mg,20%). Chromatography was performed on silica gel (20 g, 5% methanol indichloromethane eluant).

MS (ISP): 469.1 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.52 (m, 10H),7.10 (s, 1H), 3.44-3.68 (m, 2H), 3.18 (m, 2H), 2.20-2.40 (m, 4H), 2.18(s, 3H).

Example 70 Preparation of(7-bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone

From 7-bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid(100 mg, 0.23 mmol), EDCI (49 mg, 0.25 mmol) and N-methylpiperazine (50mg, 0.50 mmol), the title compound was obtained as a white solid (9 mg,8%). Chromatography was performed on silica gel (20 g, 5% methanol indichloromethane eluant).

MS (ISP): 513.1 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.52 (m, 10H),7.18 (s, 1H), 3.44-3.68 (m, 2H), 3.17 (m, 2H), 2.20-2.40 (m, 4H), 2.09(s, 3H).

Preparation of7-bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid

7-Bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid methylester (520 mg, 1.16 mmol) is dissolved in THF (6 ml). Lithium hydroxidehydrate (190 mg, 4.64 mmol) in water (6 ml) is added. After addition ofmethanol (2 ml) the reaction is heated to reflux for 5 hours. Aftercooling the organic solvents are evaporated and the reaction is dilutedwith water, acidified with 1N aqueous HCl solution and extracted withethyl acetate. The combined organic layers are washed with brine, diredover sodium sulfate and filtered. The solvent is evaporated in vacuo.The residue is stirred with n-hexane. The product precipitates as awhite solid (350 mg, 70%), which is filtered and dried.

MS (ISP): 429.1 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 13.45 (br s,1H, QH), 7.68 (s, 1H), 7.52 (m, 10H).

The preparation of7-bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid methylester is described in the literature (EP 0 544 166).

Example 71 Preparation of(7-bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

From 7-bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid(100 mg, 0.23 mmol), EDCI (49 mg, 0.25 mmol) and piperidine (50 mg, 0.50mmol), the title compound was obtained as a white solid (7 mg, 7%).Chromatography was performed on silica gel (20 g, ethyl acetate eluant).

MS (ISP): 498.1 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.52 (m, 10H),7.17 (s, 1H), 3.56 (m, 2H), 3.12 (m, 2H), 1.48-1.60 (m, 4H),1.40-1.482.09 (m, 2H).

Example 72 Preparation of(7-bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

From 7-bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid(1100 mg, 0.23 mmol), EDCI (49 mg, 0.25 mmol) and morpholine (44 mg,0.50 mmol), the title compound was obtained as a white solid (47 mg,39%). Chromatography was performed on silica gel (20 g, ethyl acetateeluant).

MS (ISP): 500.1 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.52 (m, 10H),7.23 (s, 1H), 3.42-3.70 (m, 6H), 3.19 (m, 2H).

Example 73 Preparation of(7-hydroxy-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

Piperidine (0.3 ml, 2 mmol) and ethyl diisopropylamine (0.5 ml, 3 mmol)were dissolved in methylene chloride (10 ml).7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl chloride (353 mg, 1mmol) dissolved in methylene chloride (3 ml) was added dropwise at roomtemperature. The reaction was stirred at room temperature for 24 hours.The solvent was evaporated and the residue was partitioned between ethylacetate and water. The organic layer was extracted with IN aqueous HClsolution, brine, dried over sodium sulfate and filtered. The solvent wasevaporated and the residue purified by column chromatography on silicagel (20 g, 5% methanol in dichloromethane eluant) to yield the phenol asa white solid (180 mg, 45%).

MS (ISP): 400.3 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 10.08 (s, 1H,OH), 7.52-7.55 (m, 4H), 7.41-7.48 (m, 6H), 6.52 (s, 1H), 6.46 (s, 1H),3.38 (br m, 4H), 1.59 (br m, 2H), 1.09 (br m, 4H).

The preparation of 7-hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylicacid is described in the literature (K. S. Feldman, S. M. Ensel, J. Am.Chem. Soc. 115 (3) (1993) 1162-3.)

Preparation of 7-hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonylchloride

7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (334 mg, 1mmol) was dissolved in chloroform (5 ml). One drop of triethyl amine wasadded. At 45 to 50° C. thionylchloride (0.33 ml, 4.5 mmol) was addedwithin 30 minutes. The solution was than stirred for 6 hours at 70° C.The exccess thionyl chloride was removed by evaporation. The crude7-hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl chloride was usedwithout further purification in the next step.

Example 74 Preparation of1-(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-carbonyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine

4-(4-Fluorophenyl)-1,2,3,4-tetrahydropyridine hydrochloride (106 mg, 0.5mmol) was suspended in methylene chloride (10 ml). Ethyldiisopropylamine (150 mg, 1.2 mmol) was added followed by2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid benzotriazol-1-yl ester(150 mg, 0.5 mmol). The reaction was stirred for 2 hours at roomtemperature. The solvent was evaporated and the residue was purified bycolumn chromatography on silica gel (20 g, ethyl acetate eluant). Theamide was obtained as white crystals (177 mg, 75%).

MS (ISP): 478.4 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.53-7.57 (m,4H), 7.44-7.50 (m, 8H), 7.17 (t, 2H), 7.15 (s, 1H), 7.10 (d, 1H), 7.01(d, 1H), 6.15 (br s, 1H), 4.15 (br s, CH₂), 3.62 (m, 2H), 2.52 (m, 2Hunder DMSO peak).

Example 75 Preparation of1-(2,2-diphenyl-benzo[1,3]dioxol-5-yl-methyl)-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine

Lithium aluminium hydride (13 mg, 0.36 mmol) was suspended in THF (10ml). At room temperature(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone(104 mg, 0.22 mmol) dissolved in THF (1.5 ml) was added dropwise underargon. The reaction was heated to reflux for 2 hours. Lithium aluminiumhydride (50 mg) was added and the reaction was heated to refluxovernight under argon. Lithium aluminium hydride solution (0.3 ml, 1Msolution in THF) was added and the reaction heated to reflux for 4hours. The reaction was cooled (ice bath) and under argon a mixture ofwater (0.4 ml) and THF (1.5 ml) was added slowly. The reaction wasstirred for 10 minutes and solid potassium carbonate (2 g) was added.The reaction was filtered and the filtrate was concentrated in vacuo.The residue was dissolved in ethyl acetate. The organic solution wasdried over sodium sulfate, filtered and the solvent was evaporated toyield the product as a white colorless viscous oil (85 mg, 85%).

MS (ISP): 464.4 (M+H⁺, 100). NMR (300 MHz, DMSO-D₆) ppm: 7.52-7.56 (m,4H), 7.42-7.53 (m, 7H), 7.14 (t, 2H), 6.98 (m, 2H), 6.87 (s, 1H), 6.83(d, 1H), 6.09 (br s, 1H), 3.48 (s, CH₂), 3.01 (m, 2H), 2.59 (m, 2H),2.52 (m, 2H).

Example 78 Preparation ofN-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-benzenesulfonamide

2,2-Diphenyl-1,3-benzodioxol-5-amine was dissolved in dichloromethane (5ml). N-ethyldiisopropyl amine (0.1 ml. 0.6 mmol) and benzenesulfonylchloride (88 mg, 0.5 mmol) were added. The reaction was stirred for 5hours at room temperature. The reaction was washed with cold 1N aqueousHCl, with 1N aqueous NaOH and with saturated aqueous sodium chloridesolution. The organic layer was dried over sodium sulfate, filtered andthe solvent was evaporated in vacuo. The residue was purified by columnchromatography using dichloromethane as the eluant. The product wascrystallized from hexane to yield the product as white crystals (12 mg,6%).

MS: 428.3 ([M−H]⁻).

NMR (300 MHz, DMSO-d₆) ppm: 10.05 (br, 1H, NH), 7.69 (d, 2H), 7.59 (d,1H), 7.55 (d, 2H), 7.50-7.38 (m, 10H), 6.87 (d, 1H), 6.73 (s, 1H), 6.50(d, 1H).

The following examples 79-86 (except Example 82) were prepared using themethod described for the preparation of Example 78:

Example 79 Preparation ofN,N-bis(methylsulfonyl)-2,2-diphenyl-1,3-benzodioxol-5-amine

The title compound was produced in accordance with the general method ofExample 78 from 2,2-diphenyl-1,3-benzodioxol-5-amine andmethanesulfonylchloride. Off white solid.

MS: m/e=446.4 ([M+H]⁺)

NMR (300 MHz, DMSO-d₆) ppm: 7.44-7.58 (m, 10H), 7.28 (s, 1H), 7.13 (d,1H), 7.06 (d, 1H), 3.49 (s, 6H).

Example 80 Preparation ofN,N-bis(butylsulfonyl)-2,2-diphenyl-1,3-benzodioxol-5-amine

The title compound was produced in accordance with the general method ofExample 78 from 2,2-diphenyl-1,3-benzodioxol-5-amine andbutansulfonylchloride.

MS: m/e=530.4 ([M+H]⁺).

NMR (300 MHz, DMSO-d₆) ppm: 7.44-7.58 (m, 10H), 7.22 (s, 1H), 7.12 (d,1H), 7.03 (d, 1H), 3.62 (br, 4H), 1.71 (m, 4H), 1.40 (m, 4H), 0.88 (t,6H).

Example 81 Preparation of cyclohexanecarboxylic acid(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide

The title compound was produced in accordance with the general method ofExample 78 from 2,2-diphenyl-1,3-benzodioxol-5-amine andcyclohexanecarboxylic acid chloride.

MS: m/e=400.5 ([M+H]⁺).

NMR (300 MHz, DMSO-d₆) ppm: 9.71 (br, 1H, NH), 7.41-7.56 (m, 11H), 6.97(d, 1H), 6.92 (d, 1H), 2.23 (br, 1H), 1.60-1.80 (m, 10H), 1.18-1.42 (m,10H).

Example 82 Preparation of butane-1-sulfonic acid(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide

N,N-Bis(butylsulfonyl)-2,2-diphenyl-1,3-benzodioxol-5-amine (Example 80,79 mg, 0.15 mmol) was dissolved in tetrahydrofuran (4 ml).Tetrabutylammonium fluoride solution in tetrahydrofuran (1M, 0.16 mL,0.16 mmol) was added dropwise at room temperature and the solution wasstirred at room temperature overnight. The reaction was heated to refluxfor 30 minutes, poured into water and extracted twice with ethylacetate. The combined organic layers were washed with saturated aqueoussodium chloride solution, dried over sodium sulfate, filtered and thesolvent was evaporated in vacuo. The residue was purified by columnchromatography using dichloromethane as the eluant. Crystallization fromhexane yielded the product as white crystals (45 mg, 74%).

ISN-MS: m/e=408.2 ([M+H]⁻, 100).

NMR (300 MHz, DMSO-d₆) ppm: 9.53 (br, 1H, NH), 7.55-7.42 (m, 10H), 6.98(d, 1H), 6.90 (s, 1H), 6.69 (d, 1H), 3.00 (m, 2H), 1.59 (m, 2H), 0.804(t, 3H).

Example 83 Preparation ofN-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-butyramide

The title compound was produced in accordance with the general method ofExample 78 from 2,2-diphenyl-1,3-benzodioxol-5-amine and butanoic acidchloride.

MS: m/e=360.3 ([M+H]⁺.

NMR (300 MHz, DMSO-d₆) ppm: 9.78 (br, 1H, NH), 7.41-7.55 (m, 1H), 6.94(m, 2H), 2.22 (t, 2H), 1.59 (m, 2H), 0.89 (t, 3H).

Example 84 Preparation of morpholine-4-carboxylic acid(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide

The title compound was produced in accordance with the general method ofExample 78 from 2,2-diphenyl-1,3-benzodioxol-5-amine and4-morpholincarbonylchloride.

MS: m/e=403.4 ([M+H]⁺).

NMR (300 MHz, DMSO-d₆) ppm: 8.41 (br, 1H, NH), 7.40-7.55 (m, 10H), 7.21(s, 1H), 6.89 (d, 1H), 6.83 (d, 1H), 3.58 (m, 4H), 3.37 (m, 4H).

Example 85 Preparation of piperidine-1-sulfonic acid(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide

The title compound was produced in accordance with the general method ofExample 78 from 2,2-diphenyl-1,3-benzodioxol-5-amine andpiperidine-1-sulfonyl chloride.

MS: m/e=435.3 ([M+H]⁺).

NMR (300 MHz, DMSO-d₆) ppm: 9.62 (br, 1H, NH), 7.41-7.55 (m, 10H), 6.97(d, 1H), 6.87 (s, 1H), 6.68 (d, 1H), 3.04 (m, 4H), 1.37 (m, 6H).

Example 86 Preparation of piperidine-1-carboxylic acid(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-amide

The title compound was produced in accordance with the general method ofExample 78 from 2,2-diphenyl-1,3-benzodioxol-5-amine andpiperidinecarbonyl chloride.

MS: m/e=401.4 ([M+H]⁺).

NMR (300 MHz, DMSO-d₆) ppm: 8.30 (br, 1H, NH), 7.40-7.55 (m, 10H), 7.22(d, 1H), 6.84 (m, 2H), 3.36 (m, 2H), 1.45-1.56 (m, 6H).

Example 87 Preparation of[2-(4-chloro-phenyl)-2-(2-fluoro-4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

To a mixture of 1H-benzotriazol-1-yl2,2-diphenyl-1,3-benzodioxole-5-carboxylate (300 mg, 0.689 mmol) inacetonitrile ( 2.0 mL) was added morpholine (100 mg, 1.15 mmol, 1.67eq.) at 0° C. After 10 min, the cooling bath was removed and thereaction was stirred 3 h at 20° C. The reaction was partitioned betweenwater and dichloromethane. The aqueous layer was extracted withdichloromethane. The combined organic layer was washed with brine andwater and then dried in vacuo, affording the title compound (267 mg,quant.) as a white solid.

MS: m/e=388.4 ([M+H]⁺).

1H-Benzotriazol-1-yl 2,2-diphenyl-1,3-benzodioxole-5-carboxylate wasprepared according to literature procedures (EP 544166).

Preparation of (3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone

To a cooled (0° C.) solution of(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone (270 mg,0.7 mmol) in trifluoroacetic acid (4 mL) was added triethylsilane (160mg, 1.38 mmol, 1.96 eq.). The reaction mixture was stirred 20 min at 0°C. The cooling bath was removed and the reaction mixture was stirred for4 h at R.T. The reaction mixture was evaporated. Purification by flashchromatography afforded the title compound (147 mg, 95%) as a whitesolid.

MS: m/e=220.3 ([M−H]⁻).

Preparation of (4-chloro-phenyl)-(2-fluoro-4-methoxy-phenyl)-methanone

Aluminium trichloride (144 g, 1.08 mol) was added to a cooled (0° C.)solution of nitrobenzene (450 mL). A solution of 4-chlorobenzoylchloride (128.5 mL, 1 mol) in nitrobenzene (200 mL) was slowly added.3-Fluoroanisole (108.5 mL, 0.95 mol) was slowly added. The reactionmixture was stirred overnight at 20° C., partitioned between ice waterand ethyl acetate. The aqueous layer was extracted with ethyl acetateand the combined organic phase was washed with water, dried over sodiumsulfate, filtered and concentrated in vacuo. The warm solution waspoured onto cyclohexane. The solid was filtered, washed with cyclohexaneand dried in vacuo, affording the title compound (104.5 g, 41%) as anoff-white solid.

MS: m/e=264 ([M]⁺)

Preparation of 4-chloro-2′-fluoro-4′-methoxy-dichlorodiphenylmethane

N,N-Dimethylformamide (0.031 mL, 0.4 mmol, 1 eq.) was added to asolution of (4-chloro-phenyl)-(2-fluoro-4-methoxy-phenyl)-methanone (106mg, 0.4 mmol, 1 eq.) in thionyl chloride (0.6 mL). The reaction mixturewas stirred under reflux for 18 h and the volatiles were removed invacuo, affording the title compound as an orange oil (135 mg, 87%).

NMR (300 MHz, CDCl₃) ppm: 7.82 (dd, 1H), 7.56 (d, 2H), 7.32 (dd, 2H),6.73 (dd, 1H), 6.63 (dd, 1H), 3.83 (s, 3H).

Preparation of[2-(4-chloro-phenyl)-2-(2-fluoro-4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

A solution of (3,4-dihydroxy-phenyl)-piperidin-1-yl-methanone (37.7 mg,0.169 mmol) and 2-fluoro-4-methoxy-4′-chlorodiphenyldichloromethane(67.5 mg, 0.175 mmol) in toluene (1.7 mL) was heated at reflux, during42 h. The reaction mixture was cooled down and adsorbed onto silica.Purification by flash chromatography afforded the title compound (46 mg,58%) as a yellow semisolid.

MS: m/e=470.2 ([M+H]⁺).

Example 88 Preparation of the4-[2-(4-chloro-phenyl)-2-(2-fluoro-4-methoxy-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine

Preparation of 4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-morpholine

To a solution of [3,4-[(diphenylmethylene)dioxy]phenyl]sulfonyl chloride(202 mg, 0.54 mmol) in tetrahydrofuran (2 mL) was added morpholine (52mg, 0.596 mmol, 1.1 eq.) and potassium tert-butoxide (73 mg, 0.65 mmol,1.2 eq.). The reaction mixture was stirred 48 h at 20° C. andpartitioned between an aqueous solution of hydrochloric acid (1N) anddichloromethane. The aqueous phase was extracted with dichloromethane.The combined organic layer was washed with aqueous solutions ofbicarbonate and brine. Purification by flash chromatography afforded thetitle compound (179 mg, 78%) as an off-white solid

MS: m/e=424.5 ([M+H]⁺).

[3,4-[(Diphenylmethylene)dioxy]phenyl]sulfonyl chloride was preparedaccording to literature procedures (EP 544166 and WO 9218490).

Preparation of 4-(morpholine-4-sulfonyl)-benzene-1,2-diol

The title compound was produced in accordance with the general method ofExample 87b from4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-morpholine (Example 88a).Off-white solid.

MS: m/e=257.9 ([M−H]).

Preparation of4-[2-(4-chloro-phenyl)-2-(2-fluoro-4-methoxy-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 87e from 4-(morpholine-4-sulfonyl)-benzene-1,2-diol (Example88b) and 2-fluoro-4-methoxy-4′-chlorodiphenyldichloromethane (Example87d). White solid.

MS: m/e=506.9 ([M+H]⁺).

Example 89 Preparation of[2-(4-methoxy-phenyl)-2-(3-nitro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of (4-methoxyphenyl)-(3-nitrophenyl)-methanone

To a cold (0° C.) mixture of anisole (17.7 mL, 0.162 mol, 1.0 eq.) andaluminium trichloride (26.9 g, 0.202 mol, 1.25 eq.) in1,2-dichloroethane (140 mL) was slowly added 3-nitrobenzoylchloride (30g, 0.162 mol). The cooling bath was removed, and the reaction mixturewas stirred 2 h at 20° C. The reaction mixture was poured into icewater. Concentrated hydrochloric acid (5 mL) was added. The aqueouslayer was extracted with dichloromethane (2 times). The combined organiclayers were dried over sodium sulfate, filtered and the volatiles wereremoved in vacuo. Purification by flash chromatography afforded thetitle compound (35.1 g, 84%) as an orange solid, m.p.: 88-89° C.

Preparation of 4-methoxy-3′-nitro-dichlorodiphenylmethane

The title compound was produced in accordance with the general method ofExample 87d from (4-methoxyphenyl)-(3-nitrophenyl)-methanone (Example89a). Yellow oil.

NMR (300 MHz, CDCl₃) ppm: 8.53-8.52 (m, 1H), 8.23 (dd, 1H), 7.95 (dd,1H), 7.59-7.50 (m, 3H), 6.89 (d, 2H), 3.85 (s, 3H).

Preparation of[2-(4-methoxy-phenyl)-2-(3-nitro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 87e from (3,4-dihydroxy-phenyl)-morpholine-1-yl-methanone(Example 87b) and 4-methoxy-3′-nitro-dichlorodiphenylmethane (Example89b). White foam.

MS: m/e=463.3([M+H]⁺).

Example 90 Preparation of[4-[2-(4-methoxy-phenyl)-2-(3-nitro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 108c from 4-(Morpholine-4-sulfonyl)-benzene-1,2-diol (Example88b) and 4-methoxy-3′-nitro-dichlorodiphenylmethane (Example 89b). Lightyellow oil.

MS: m/e=499 ([M+H]⁺).

Example 91 Preparation of[4-[2-(4-methoxy-phenyl)-5-(morpholine-4-carbonyl)-benzo[1,3]dioxol-2-yl]-benzonitrile

Preparation of 4-(4-methoxy-benzoyl)-benzonitrile

The title compound was produced in accordance with the general method ofExample 87d from 4-(4-methoxy-benzoyl)-benzonitrile. Yellow oil. NMR(300 MHz, CDCl₃) ppm: 7.70-7.60 (m, 4H), 7.43 (d, 2H), 6.82 (d, 2H),3.77 (s, 3H).

Preparation of 4-cyano-4-methoxy-dichlorodiphenylmethane

The title compound was produced in accordance with the general method ofExample 87d from 4-(4-methoxy-benzoyl)-benzonitrile (Example 91a).Yellow oil.

MS: m/e=443.4 ([M+H]⁺).

Preparation of4-[2-(4-methoxy-phenyl)-5-(morpholine-4-carbonyl)-benzo[1,3]dioxol-2-yl]-benzonitrile

The title compound was produced in accordance with the general method ofExample 87e from (3,4-dihydroxy-phenyl)-morpholine-1-yl-methanone(Example 87b) and 4-cyano-4-methoxy-dichlorodiphenylmethane (Example91b). Yellow oil

MS: m/e=443.4 ([M+H]⁺).

Example 92 Preparation of4-[2-(4-methoxy-phenyl)-5-(morpholine-4-sulfonyl)-benzo[1,3]dioxol-2-yl]-benzonitrile

The title compound was produced in accordance with the general method ofExample 88c from 4-(morpholine-4-sulfonyl)-benzene-1,2-diol (Example88b) and 4-cyano-4-methoxy-dichlorodiphenylmethane (Example 91b).Off-white foam.

MS: m/e=479.3 ([M+H]⁺).

Example 93 Preparation of[2-(2-fluoro-4-methoxy-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of (2-fluoro-4-methoxy-phenyl)-(4-fluoro-phenyl)-methanone

To a cold (5° C.) mixture of aluminium trichloride (144 g, 1.08 mol,1.13 eq.) in nitrobenzene (450 mL) was slowly added a solution of4-fluorobenzoyl chloride (120 mL, 1 mol, 1.05 eq.) in nitrobenzene (200mL). 3-fluoroanisole (108.5 mL, 0.95 mol) was slowly added to thereaction mixture. The cooling bath was removed and the reaction mixturewas stirred 3 h at 20° C., and poured into ice-water. The aqueous layerwas extracted with dichloromethane (2 times). The combined organiclayers were dried over sodium sulfate, filtered and the volatiles wereremoved in vacuo. The crude mixture was crystallized in cyclohexane,filtered and the solid was washed with cyclohexane. The solid was driedin vacuo, affording the title compound (57.78 g, 25%) as a white solid.

m.p.: 89.7-90.1° C.

Preparation of 2-fluoro-4-methoxy-4′-fluoro-dichlorodiphenylmethane

The title compound was produced in accordance with the general method ofExample 87d from (2-fluoro-4-methoxy-phenyl)-(4-fluoro-phenyl)-methanone(Example 93a). Yellow semisolid.

MS: m/e=304.2 ([M+H]⁺).

Preparation of[2-(2-fluoro-4-methoxy-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 87e from (3,4-dihydroxy-phenyl)-morpholine-1-yl-methanone(Example 87b) and 2-fluoro-4-methoxy-4′-fluoro-dichlorodiphenylmethane(Example 93b). Brown oil.

MS: m/e=454.5 ([M+H]⁺).

Example 94 Preparation of4-[2-(2-fluoro-4-methoxy-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 88c from 4-(morpholine-4-sulfonyl)-benzene-1,2-diol (Example88b) and 2-fluoro-4-methoxy-4′-fluoro-dichlorodiphenylmethane (Example93b). White foam.

MS: m/e=490.3 ([M+H]⁺).

Example 95 Preparation of(6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

Preparation of 2-fluoro-4,5-dihydroxy-benzaldehyde

To a cooled (−78° C.) solution of 6-fluoroveratraldehyde (2 g, 10.9mmol) in dichloromethane (40 mL) was added a solution of borontribromide in dichloromethane (1M, 44 mL, 44 mmol, 4.0 eq.). Thereaction was allowed to reach room temperature and was stirredovernight. The reaction mixture was partitioned between ice water anddiethyl ether. The aqueous layer was extracted with diethyl ether. Thecombined organic layer was washed with water dried over sodium sulfateand filtered. Volatiles were removed in vacuo. Purification by flashchromatography afforded the title compound (1.71 mg, quant.) as a darksolid

MS: m/e=156.0 ([M]⁺).

Preparation of 4,5-bis-benzyloxy-2-fluoro-benzaldehyde

To a solution of 2-fluoro-4,5-dihydroxy-benzaldehyde (44.0 g, 282 mmol)in acetone (1 L) was added potassium carbonate (39.0 g, 0.282 mmol, 1.0eq.) and benzylbromide (33.5 mL, 0.282 mmol, 1.0 eq.). The reactionmixture was stirred overnight at 20° C. The mixture was filtered on apad of dicalite. After evaporation, purification by flash chromatographyafforded the title compound (5.34 g, 6%) as a white solid.

MS: m/e=336.1 ([M]).

Preparation of 4,5-bis-benzyloxy-2-fluoro-benzoic acid

To a cold (0° C.) solution of 4,5-bis-benzyloxy-2-fluoro-benzaldehyde(2.15 g, 6.39 mmol) in acetone (86.0 mL) was slowly added Jones reagent(4.3 mL). The reaction mixture was stirred 19 h at 0° C. Propanol (0.43mL) was added and the reaction mixture was stirred 40 min at 20° C. Thecrude mixture was filtered, washed with acetone and poured into water(50 mL). The solid was filtered, washed with water and dried in vacuo,yielding the title compound (1.82 g, 81%) as a white solid.

MS: m/e=351.1 ([M−H]⁻)

Jones' reagent: to a cold (0° C.) solution of chromium oxide (826 mg,8.3 mmol) in water (1.3 mL) was slowly added concentrated sulfuric acid(0.86 mL). The solution was diluted with water (2.15 mL).

Preparation of(4,5-bis-benzyloxy-2-fluoro-phenyl)-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from 4,5-bis-benzyloxy-2-fluoro-benzoic acid (Example 95c)and piperidine. White solid.

MS: m/e=420.5 ([M+H]⁺).

Preparation of (2-fluoro-4,5-dihydroxy-phenyl)-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 87b from(4,5-bis-benzyloxy-2-fluoro-phenyl)-piperidin-1-yl-methanone (Example95d). Colorless semisolid.

MS: m/e=240.2 ([M+H]⁺).

Preparation of(6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-piperidin-1-yl-methanone (Example 95e)and dichlorodiphenylmethane. Colorless semisolid.

MS: m/e=404.3 ([M+H]⁺).

Example 96 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-piperidin-1-yl-methanone (Example 95e)and 2,4-dichloro-4′-fluoro-chlorodiphenyldichloromethane (Example 108b).White solid.

MS: m/e=404.3([M−C₅H₁₀N*]⁺)

Example 97 Preparation of[6-fluoro-2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of 4-fluorodiphenyldichloromethane

The title compound was produced in accordance with the general method ofExample 108b from benzotrifluoride and fluorobenzene. Yellow oil.

NMR (300 MHz, CDCl₃) ppm: 7.63-7.57 (m, 4H), 7.38-7.35 (m, 3H),7.06-7.00 (m, 2H).

Preparation of[6-fluoro-2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-piperidin-1-yl-methanone (Example 95e)and 4-fluorodiphenyldichloromethane (Example 97a). White solid.

MS: m/e=422.2 ([M+H]⁺).

Example 98 Preparation of[2-(2-chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of 2-chloro-4′-methoxy-diphenyldichloromethane

The title compound was produced in accordance with the general method ofExample 108b from 2-chlorobenzotrifluoride and anisole. Brown oil.

NMR (300 MHz, CDCl₃) ppm: 7.46-7.35 (m, 6H), 6.85 (d, 2H), 3.83 (s, 3H).

Preparation of[2-(2-chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from[2-(2-chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone(Example 95e) and 2-chloro-4′-methoxy-diphenyldichloromethane (Example98a). White solid.

MS: m/e=468.1 ([M+H]⁺).

Example 99 Preparation of(6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

Preparation of(4,5-bis-benzyloxy-2-fluoro-phenyl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from 4,5-bis-benzyloxy-2-fluoro-benzoic acid (Example 95c)and morpholine. White solid.

MS: m/e=421.1 ([M+H]⁺).

Preparation of (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 87b from(4,5-bis-benzyloxy-2-fluoro-phenyl)-morpholin-4-yl-methanone (Example99a). White solid.

MS: m/e=242.2 ([M+H]⁺).

Preparation of(6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 99b)and dichlorodiphenylmethane. White solid.

MS: m/e=406.2 ([M+H]⁺).

Example 100 Preparation of[6-fluoro-2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 99b)and 4-fluorodiphenyldichloromethane (Example 97a). White solid.

MS: m/e=424.3 ([M+H]⁺).

Example 101 Preparation of[2-(2-chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 99b)and 2-chloro-4′-methoxy-diphenyldichloromethane (Example 98a). Whitesolid.

MS: m/e=424.3 ([M+H]⁺).

Example 102 Preparation of(6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone

Preparation of(4,5-bis-benzyloxy-2-fluoro-phenyl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108e from 4,5-bis-benzyloxy-2-fluoro-benzoic acid (Example 95c)and 1-(4-fluorophenyl)piperazine. Light yellow solid.

MS: m/e=514.6 ([M+H]⁺).

Preparation of(2-fluoro-4,5-dihydroxy-phenyl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone

The title compound was produced in accordance with the general method ofExample 87b from(4,5-bis-benzyloxy-2-fluoro-phenyl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone(Example 102a). White solid.

MS: m/e=335.2 ([M+H]⁺).

Preparation of(6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone(Example 102b) and dichlorodiphenylmethane. Light brown solid.

MS: m/e=499.2 ([M+H]⁺).

Example 103 Preparation of[6-fluoro-2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxol-5-yl]-[4-4-fluoro-phenyl)-piperazin-1-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone(Example 102b) and 4-fluorodiphenyldichloromethane (Example 97a). Greysolid.

MS: m/e=517.2 ([M+H]⁺).

Example 104 Preparation of[2-(2-chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone(Example 102b) and 2-chloro-4′-methoxy-diphenyldichloromethane (Example98a). Orange solid.

MS: m/e=563.2 ([M]⁺).

Example 105 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of 2,4-dichloro-4′-methoxy-diphenyldichloromethane

The title compound was produced in accordance with the general method ofExample 108b from 2,4-dichlorobenzotrifluoride and anisole. Red oil.

NMR (300 MHz, CDCl₃) ppm: 8.22 (d, 1H), 7.43-7.29 (m, 4H), 6.85 (d, 2H),3.73 (s, 3H).

Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-piperidin-1-yl-methanone (Example 95e)and 2,4-dichloro-4′-methoxy-diphenyldichloromethane (Example 105a).Orange oil.

MS: m/e=502.3 ([M+H]⁺).

Example 106 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 99b)and 2,4-dichloro-4′-methoxy-diphenyldichloromethane (Example 105a).Yellow oil.

MS: m/e=504.3 ([M+H]⁺).

Example 107 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone(Example 102b) and 2,4-dichloro-4′-methoxy-diphenyldichloromethane(Example 105a). Brown oil.

MS: m/e=597.2 ([M]⁺).

Example 108 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of 4-bromo-5-fluoro-benzene-1,2-diol

To a cooled (−78° C.) solution of 4-fluoroveratrole (5.0 g, 32 mmol) indichloromethane (106 mL) was slowly added a solution of tribromoboranein dichloromethane (1M, 96 mL, 96 mmol, 3.0 eq.). The reaction mixturewas warmed to 20° C. and stirred overnight. The reaction mixture waspoured into ice water, extracted with ethyl acetate (3 times). Thecombined organic layer was washed with an aqueous solution of sodiumbicarbonate, dried over sodium sulfate and filtered. The volatiles wereremoved in vacuo. The brown solid was diluted with chloroform (50 mL)and dichloromethane (10 mL). A solution of bromine in carbontetrachloride (5 ml) was slowly added. After 3 hours, the volatiles wereremoved in vacuo. Purification by flash chromatography afforded thetitle compound (6.51 g, 98%) as a brown solid

MS: m/e=207.9 ([M+H]⁺).

Preparation of 2,4-dichloro-4′-fluoro-diphenyldichloromethane

To a cooled (0° C.) suspension of aluminium trichloride (2.02 g, 15mmol, 3.0 eq.) in 1,2-dichloroethane (7 mL) was slowly added2,4-dichlorobenzotrifluoride (1.1 g, 5 mmol) followed by fluorobenzene(0.483 g, 5 mmol, 1.0 eq.). The reaction mixture was stirred at 0-5° C.for 5 h, then poured onto ice and extracted with dichloromethane. Thecombined organic layer was washed with brine, dried over sodium sulfateand filtered. The volatiles were removed in vacuo, affording the titlecompound (1.63 g, quant.) as yellow oil.

MS: m/e=325.0 ([M+H]⁺).

Preparation of5-bromo-2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole

A mixture of 4-bromo-5-fluoro-benzene-1,2-diol (6.43 g, 31.1 mmol) and2,4-dichloro-4′-fluoro-chlorodiphenyldichloromethane (10.07 g, 31.1mmol, 1.0 eq.) was heated under stirring at 180° C. for 20 min. Thereaction mixture was cooled to 20° C., diluted with dichloromethane andadsorbed onto silica. Purification by flash chromatography afforded thetitle compound (9.98 g, 70%) as a light yellow solid.

MS: m/e=457.9 ([M+H]⁺).

Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid

To a cooled (-78° C.) solution of5-bromo-2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole(16.5 g, 36.0 mmol) in diethyl ether (250 mL) was slowly added asolution of n-butyl lithium in hexanes (1.6M, 23 mL, 36.0 mmol, 1.0eq.). After 1 h at −78° C., solid carbon dioxide (50 g approx.) wasadded to the solution and the reaction was allowed to warm up to 20° C.After 16 h at 20° C. the reaction mixture was partitioned between water(150 mL), ethyl acetate (1.5 L) and hydrochloric acid (1N, 150 mL). Theaqueous layer was extracted with ethyl acetate and the combined organiclayers were washed with water. The volatiles were removed in vacuo.Purification by flash chromatography afforded the title compound (10.73g, 69%) as a light yellow solid.

MS: m/e=422.3 ([M−H]⁻).

Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

To a solution of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (380 mg, 0.898 mmol) in N,N-dimethylformamide (7 mL) was addedcarbonyldiimidazole (189 mg, 1.17 mmol, 1.3 eq.). The reaction mixturewas stirred 16 h at 20° C.

Morpholine (196 mg, 2.24 mmol, 2.5 eq.) was added and the reaction wasstirred 8 h at 90° C. The reaction mixture was partitioned betweenhydrochloric acid (1N) and ethyl acetate. The organic layer was washedwith brine and water the volatiles were removed in vacuo. Purificationby flash chromatography afforded the title compound (367 mg, 83%) as awhite solid.

MS: m/e=493.43 ([M+H]⁺).

Example 110 Preparation of(6-methyl-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

Preparation of 4-bromo-5-methylpyrocatechol

To a solution of homoveratrole (136.4 g, 1.1 mol) in chloroform (1.2 L)and dichloromethane (300 mL) was slowly added a solution of bromine (66mL, 1.28 mol, 1.2 eq.) in carbon tetrachloride (250 mL). After 5 hoursthe reaction mixture was neutralized to pH7 with an aqueous solution ofsodium hydroxide and the aqueous layer was extracted with chloroform.The combined organic layer was dried over sodium sulfate, filtered, andthe volatiles were removed in vacuo, affording the title compound as alight brown solid, m.p.: 92-98° C.

Preparation of 5-bromo-6-methyl-2,2-diphenyl-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c from 4-bromo-5-methylpyrocatechol anddiphenyldichloromethane. White solid.

MS: m/e=368.0 ([M+H⁺]).

Preparation of 6-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxylic acidlithium salt

To a cold (−70° C.) solution of5-bromo-6-methyl-2,2-diphenyl-benzo[1,3]dioxole (Example 110b, 91.8 g,250 mmol) in tetrahydrofuran (140 mL) was slowly added a solution ofn-butyl lithium in hexanes (170 mL, 1.6 M, 1.1 eq.) and tetrahydrofuran(100 mL). After 15 min, an excess of solid carbon dioxide was added. Thereaction was allowed to warm to room temperature. The solid was filteredand dried in vacuo, affording the title compound (79.4 g, 77%) as awhite solid.

MS: m/e=345.2 ([M +2Li]).

Preparation of(6-methyl-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

To a solution of 6-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxylicacid lithium salt (101.5 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL)was addedN,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-uronium-hexafluorophosphate(114 mg, 0.3 mmol, 1.0 eq.). The reaction mixture was stirred 1 h at 20°C. Piperidine (26 mg, 0.3 mmol, 1.0 eq.) was added and the reactionmixture was stirred 20 h at 20° C. The reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was extracted withethyl acetate. The combined organic layer was washed with water, brineand then dried over sodium sulfate, filtered and evaporated.Purification by flash chromatography afforded the title compound (73 mg,61%) as a light yellow solid.

MS: m/e=400.2

Example 111 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of 4,4′-difluoro-diphenyldichloromethane

The title compound was produced in accordance with the general method ofExample 88d from 4,4′-difluorobenzophenone. Yellow oil.

MS: m/e=272 ([M−H]⁺).

Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from (3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone(Example 87b) and 4,4′-difluoro-diphenyldichloromethane (Example 111a).White foam.

MS: m/e=442.3 ([M+H]⁺).

Example 112 Preparation of(6-bromo-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

Preparation of 6-bromo-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid

To a solution of 5-bromo-6-methyl-2,2-diphenyl-benzo[1,3]dioxole (5.20g, 14.1 mmol, Example 110b) in pyridine (52 mL) and water (26 mL) wasadded potassium permanganate (6.71 g, 42.5 mmol, 3.0 eq.) at roomtemperature. After 3 hours, the reaction mixture was partitioned betweenethyl acetate and hydrochloric acid (1N). The aqueous layer wasextracted with ethyl acetate. After evaporation, the residue wasadsorbed onto silica. Purification by flash chromatography afforded thetitle compound (4.656 g, 83%) as an off white solid.

MS: m/e=395.0 ([M−H]⁻).

Preparation of(6-bromo-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from 6-bromo-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylicacid (Example 112a) and piperidine. White solid.

MS: m/e=464.1 ([M+H]⁺)

Example 113 Preparation of(+)-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced by preparative chiral HPLC (ChiralPakAD) from racemic[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone(Example 108e). White solid.

MS: m/e=493.3 ([M+H]⁺).

Example 114 Preparation of(−)-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced by preparative chiral HPLC (ChiralPakAD) from racemic[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone(Example 108e). White solid.

MS: m/e=493.3 ([M+H]⁺).

Example 115 Preparation of[2-(2,4-dichloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The tide compound was produced in accordance with the general method ofExample 108c from 2,4-dichloro-4′-fluoro-diphenyldichloromethane(Example 108b) and (3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone(Example 87b). Light yellow gum.

MS: m/e=474.1 ([M+H]⁺).

Example 116 Preparation of[2-(2,4-dichloro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,4-dichloro-4′-fluoro-diphenyldichloromethane(Example 108b) and (3,4-dihydroxy-phenyl)-piperidin-4-yl-methanone.Light yellow gum.

MS: m/e=472.2 ([M+H]⁺).

Example 117 Preparation of(6-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

Preparation of (6-chloro-benzo[1,3]dioxol-5-yl)-piperidin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 218c from 6-chloro-1,3-benzodioxole-5-carboxylic acid andpiperidine. Colorless solid, m.p.: 138-139° C.

MS: m/e=267.9 ([M+H]⁺).

Preparation of (2-chloro-4,5-dihydroxy-phenyl)-piperidin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 218b from(6-chloro-benzo[1,3]dioxol-5-yl)-piperidin-4-yl-methanone (Example117a). Light grey solid.

MS: m/e=256.1 ([M+H]⁺).

Preparation of(6-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from □□□-diphenyldichloromethane and(2-chloro-4,5-dihydroxy-phenyl)-piperidin-4-yl-methanone (Example 117b).Colorless solid.

MS: m/e=418.1 ([M]⁺).

Example 118 Preparation of(6-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from □□□-diphenyldichloromethane and(2-chloro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 218b).White solid.

MS: m/e=422.0 ([M+H]⁺).

Example 119 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid ethyl-methyl-amide

To a solution of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d, 220 mg; 0.52 mmol; 1 eq.) in N,N-dimethylformamide(5 mL), was added carbonyl diimidazole (110 mg; 0.68 mmol; 1.3 eq.) andthe mixture stirred 2 h at 20° C. A solution of ethyl-methylamine inN,N-dimethylformamide (1M, 1 mL; 1.3 mmol; 2.5 eq.) was added and thereaction mixture stirred 4 days at 20° C. Purification by preparativeHPLC (YMC pro C18) afforded the title compound as 10 mM DMSO stocksolution.

MS: m/e=464.2 ([M]⁺).

Example 120 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid methyl-propyl-amide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and methyl-propylamine.

MS: m/e=478.2 ([M]⁺)

Example 121 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2-methyl-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 2-methyl-pyrrolidine.

MS: m/e=490.2 ([M]⁺)

Example 122 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid azepan-1-ylamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 1-aminohomopiperidine.

MS: m/e=519.3 ([M]⁺).

Example 123 Preparation ofazetidin-1-yl-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and azetidine.

MS: m/e=462.2 ([M]⁺).

Example 124 Preparation ofazepan-1-yl-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and azacycloheptane.

MS: m/e=504.2 ([M]⁺).

Example 125 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (2,2-dimethyl-1-methylcarbamoyl-propyl)-amide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and L-tert-leucine-N-methylamide.

MS: m/e=549.4 ([M]⁺).

Example 126 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2S-methoxymethyl-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 2S-methoxymethyl-pyrrolidine.

MS: m/e=520.4 ([M]⁺)

Example 127 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2R-hydroxymethyl-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 2R-hydroxymethyl-pyrrolidine.

MS: m/e=506.2 ([M]⁺).

Example 128 Preparation of1-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-bezno[1,3]dioxole-5-carbonyl]-pyrrolidine-2R-carboxylicacid dimethylamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 2R-carboxylic acid dimethylamine pyrrolidine.

MS: m/e=547.3 ([M]⁺).

Example 129 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid cyclobutylamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and cyclobutylamine.

MS: m/e=476.3 ([M]⁺).

Example 130 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid morpholin-4-ylamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and N-aminomorpholine.

MS: m/e=507.2 ([M]⁺).

Example 131 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 1-(2-pyrazinyl)-piperazine.

MS: m/e=569.3 ([M]⁺)

Example 132 Preparation of1-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carbonyl]-pyrrolidine-2S-carboxylicacid amide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and pyrrolidine-2S-carboxylic acid amide.

MS: m/e=519.3 ([M]⁺).

Example 133 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid tert-butoxy-amide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and tert-butoxy-amine.

MS: m/e=494.2 ([M]⁺).

Example 134 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid cyclopentylamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and cyclopentylamine.

MS: m/e=490.3 ([M]⁺).

Example 135 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (tetrahydro-furan-2-ylmethyl)-amide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and (tetrahydro-furan-2-ylmethyl)-amine.

MS: m/e=506.2 ([M]⁺).

Example 136 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and thiomorpholine.

MS: m/e=508.2 ([M]⁺).

Example 137 Preparation of²-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid isopropylamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and isopropylamine.

MS: m/e=464.2 ([M]⁺).

Example 138 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid pyrrolidin-1-ylamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and pyrrolidinamine.

MS: m/e=491.3 ([M]⁺).

Example 139 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid methoxy-methyl-amide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and methoxy-methyl-amine.

MS: m/e=466.2 ([M]⁺).

Example 140 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3R-hydroxy-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 3R-hydroxy-pyrrolidine.

MS: m/e=492.2 ([M]⁺).

Example 141 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid bis-cyclopropylmethyl-amide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and bis-cyclopropylmethyl-amine.

MS: m/e=530.2 ([M]⁺).

Example 142 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-fluoro-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 4-fluoro-piperidine.

MS: m/e=530.2 ([M]⁺).

Example 143 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 1,4-dioxa-8-azaspiro(4.5)decane.

MS: m/e=548.3 ([M]⁺).

Example 144 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-hydroxymethyl-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 4-hydroxymethyl-piperidine.

MS: m/e=520.3 ([M]⁺).

Example 145 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 4-hydroxy-4-methyl-piperidine.

MS: m/e=520.3 ([M]⁺).

Example 146 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and pyrrolidine.

MS: m/e=476.1 ([M]⁺).

Example 147 Preparation ofN-{1-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carbonyl]-pyrrolidin-3S-yl}-acetamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 3S-acetamidopyrrolidine.

MS: m/e=533.2 ([M]⁺).

Example 148 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid cycloheptylamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and cycloheptylamine.

MS: m/e=518.3 ([M]⁺).

Example 149 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid N′-pyridin-2-yl-hydrazide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 2-hydrazinopyridine.

MS: m/e=514.3 ([M]⁺).

Example 150 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (2S-methoxymethyl-pyrrolidin-1-yl)-amide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 2S-methoxymethyl-pyrrolidin-1-amine.

MS: m/e=534.2 ([M]⁺).

Example 151 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 1,1-dioxo-1-thiomorpholine.

MS: m/e=540.4 ([M]⁺).

Example 152 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and nortropine.

MS: m/e=532.2 ([M]⁺).

Example 153 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2R-methoxymethyl-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 2R-methoxymethyl-pyrrolidine.

MS: m/e=520.2 ([M]⁺).

Example 154 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3S-hydroxy-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 3S-hydroxy-pyrrolidine.

MS: m/e=492.2 ([M]⁺).

Example 155 Preparation ofN-{1-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carbonyl]-pyrrolidin-3R-yl}-acetamide

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 3R-acetamido-pyrrolidine.

MS: m/e=533.3 ([M]⁺).

Example 156 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2S-hydroxymethyl-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 119 from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 2S-hydroxymethyl-pyrrolidine.

MS: m/e=506.2 ([M]⁺).

Example 157 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanethione

[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone(Example 108e, 79 mg, 0.16 mmol) and Lawesson's reagent (33 mg, 0.08mmol) were heated in benzene (1 mL) under reflux for 4 h. The reactionmixture was evaporated in vacuo. Purification by flash chromatographyafforded the title compound (75 mg, 92%) as a yellow oil.

MS: m/e=508.0 ([M]⁺).

Example 158 Preparation of[2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of 2,4,4′-trichlorodiphenyldichloromethane

The title compound was produced in accordance with the general method ofExample 108b from 2,4-dichloro-benzotrifluoride and chlorobenzene. Brownoil.

MS: m/e=339.9 ([M]⁺).

Preparation of5-bromo-2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c from 4-bromo-5-fluoro-benzene-1,2-diol (Example 108a) and2,4,4′-trichlorodiphenyldichloromethane (Example 158a). White solid.

MS: m/e=473.9 ([M]⁺).

Preparation of2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid

The title compound was produced in accordance with the general method ofExample 108d from5-bromo-2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole(Example 158b). Orange solid.

MS: m/e=437.0 ([M−H]⁻).

Preparation of[2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 158c) and morpholine. Orange solid.

MS: m/e=508.3 ([M+H]⁺).

Example 159 Preparation of6-(morpholine-4-carbonyl)-2,2-diphenyl-benzo[1,3]dioxole5-carbonitrile

Preparation of(6-bromo-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from 6-bromo-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylicacid (Example 110c) and morpholine. White solid.

MS: m/e=466.2 ([M+H]⁺).

Preparation of6-(morpholine-4-carbonyl)-2,2-diphenyl-benzo[1,3]dioxole-5-carbonitrile

A mixture of(6-bromo-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone,(204 mg, 0.437 mmol) and copper cyanide (102 mg, 1.139 mmol, 2.6 eq.) inN-methyl pyrrolidinone (3 mL) was heated at 190° C. during 16 h. Thereaction mixture partitioned between water and ethyl acetate. Theorganic layer was washed with brine and evaporated in vacuo.Purification by flash chromatography afforded the title compound (4.656g, 83 %) as an off white solid.

MS: m/e=413.1 ([M+H]⁺).

Example 160 Preparation of[2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 158c) and piperidine. White solid.

MS: m/e=506.0 ([M+H]⁺).

Example 161 Preparation of[2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from2-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 158c) and pyrrolidine. Off-white solid.

MS: m/e=491.9 ([M+H]⁺).

Example 162 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of 2,2′,4,4′-tetrafluorodiphenyldichloromethane

Aluminium trichloride (5.32 g, 39.9 mmol) was added to1,3-difluorobenzene (8 g, 70.12 mmol) with stirring. The mixture wascooled to ca. 10° C. and carbon tetrachloride (14.5 mL) was addeddropwise over a period of 1 h. The mixture was stirred 3.5 h at 30° C.,diluted with dichloromethane and poured onto ice. The phases wereseparated, the organic phase dried over magnesium sulfate and evaporatedto afford the title compound as a light brown solid that was usedwithout further purification.

MS: m/e 273.0 ([M−Cl]⁻).

Preparation of[2,2-bis-(2,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,2′,4,4′-tetrafluorodiphenyldichloromethane and(3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 87b). Lightbrown gum.

MS: m/e=460.1 ([M+H]⁺).

Example 163 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,2′,4,4′-tetrafluorodiphenyldichloromethane (Example162a) and (3,4-dihydroxy-phenyl)-piperidin-4-yl-methanone. Yellow foam.

MS: m/e=458.3 ([M+H]⁺).

Example 164 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone

Preparation of5-bromo-6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c from 4-bromo-5-fluoro-benzene-1,2-diol (Example 108a) and4,4′-difluorodiphenyldichloromethane (Example 111a). Colorless oil.

MS: m/e=407.9 ([M]⁺).

Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 166b from5-bromo-6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole (Example164a) and 1-pyrrolidine-carbonyl chloride. Light yellow oil.

MS: m/e=426.3 ([M+H]⁺).

Example 165 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 166b from5-bromo-6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole (Example164a) and 1-piperidine-carbonyl chloride. Yellow oil.

MS: m/e=440.3 ([M+H]⁺).

Example 166 Preparation of[2,2-bis-(4-bromo-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of 5-bromo-6-fluoro-2,2-diphenyl-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c from 4-Bromo-5-fluoro-benzene-1,2-diol (Example 108a) anddiphenyldichloromethane. Off white solid.

MS: m/e=370.0 ([M+H⁺]).

Preparation of(6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

To a cooled (−78° C.) solution of5-bromo-6-fluoro-2,2-diphenyl-benzo[1,3]dioxole (17.59 g, 47.4 mmol) indiethyl ether (300 mL) was slowly added a solution of n-butyl lithium inhexanes (1.6M, 30 mL, 48 mmol, 1.0 eq.). The reaction mixture wasstirred 1 h at −78° C. before the addition of4-morpholinecarbonylchloride (8.5 g, 56.9 mmol, 1.2 eq.). The reactionmixture was allowed to warm to 20° C. and poured into an aqueoussolution of sodium bicarbonate. The aqueous layer was extracted withethyl acetate. The combined organic layers were washed with brine.Volatiles were removed in vacuo. Purification by flash chromatographyafforded the title compound (13.0 g, 68%) as a light yellow solid.

MS: m/e=406.2 ([M+H]⁺).

Preparation of (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 87b from(6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone.Light brown solid.

MS: m/e=442.2 ([M+H]⁺).

Preparation of 4,4′-dibromodiphenyldichloromethane

The title compound was produced in accordance with the general method ofExample 108b from 4-bromobenzotrifluoride and bromobenzene. Light yellowsemisolid.

MS: m/e=392.0 ([M+H]⁺).

Preparation of[2,2′-bis-(4-bromo-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 166c)and 4,4′-dibromodiphenyldichloromethane (Example 166d). Light yellowsolid.

MS: m/e=364.1 ([M+H]⁺).

Example 167 Preparation of4-[2,2-bis-(4-cyano-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carbonyl]-morpholine

A mixture of[2,2′-bis-(4-bromo-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone(Example 166e, 400 mg, 0.71 mmol, 1.0 eq.), copper cyanide (381 mg, 4.26mmol, 6.0 eq.), tris(dibenzylideneacetone)dipalladium (32.5 mg, 0.035mmol, 0.05 eq.), tetraethylammonium cyanide (111 mg, 0.71 mmol, 1.0 eq.)and 1,1′-bis(diphenylphosphino)ferrocene (78.7 mg, 0.142 mmol, 0.2 eq.)was flushed with nitrogen. Degassed dioxane (10 mL) was added and thereaction mixture was heated to reflux during 4 h. The reaction mixturewas diluted with ethyl acetate, filtered and washed with an aqueoussolution of sodium bicarbonate, brine and water. Volatiles were removedin vacuo. Purification by flash chromatography afforded the titlecompound (141 mg, 44%) as a light yellow semisolid.

MS: m/e=456.1 ([M+H⁺]).

Example 168 Preparation of4-[2-(4-bromo-phenyl)-5-fluoro-6-(morpholine-4-carbonyl)-benzo[1,3]dioxol-2-yl]-benzonitrile

The title compound was produced in accordance with the general method ofExample 167, as a side product. Light yellow solid.

MS: m/e=509.0 ([M+H⁺]).

Example 169 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,2′,4,4′-tetrafluorodiphenyldichloromethane (Example162a) and (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone(Example 99b). Light brown gum.

MS: m/e=478.1 ([M+H]⁺).

Example 170 Preparation of[2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of dichlorobis(4-chlorophenyl)methane

The title compound was produced in accordance with the general method ofExample 87d from 4,4′-dichlorobenzophenone and used without furtherpurification. Yellow solid.

MS: m/e=304.0, 306.0 ([M]⁺).

Preparation of[2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from dichlorobis(4-chlorophenyl)methane and2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 166c).Beige foam.

MS: m/e=474.0, 476.0 ([M]⁺).

Example 171 Preparation of[6-chloro-2,2-bis-(2,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Example 172 Preparation of[2-(2-chloro-4-fluoro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

2-Chloro-1-[dichloro-(4-fluoro-phenyl)-methyl]-4-fluoro-benzene

(2-Chloro-4-fluoro-phenyl)-(4-fluoro-phenyl)-methanone (0.25 g, 0.99mmol) and phosphorus pentachloride (0.21 g,1.01 mmol) were mixed underargon and heated 2 h at 150° C. The mixture was allowed to cool to roomtemperature, diluted with dichloromethane and poured onto ice. Thephases were separated, the organic phase dried over magnesium sulfateand evaporated to afford the title compound as a pale yellow oil (0.2 g)containing ca 50% of the desired product by NMR, along with startingmaterial (35%) and mono-chlorinated compound (15%). This mixture wasused without further purification.

Preparation of[2-(2-chloro-4-fluoro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from2-chloro-1-[dichloro-(4-fluoro-phenyl)-methyl]-4-fluoro-benzene (Example172a) and (3,4-dihydroxy-phenyl)-piperidin-4-yl-methanone. Light browngum.

MS: m/e=456.1 ([M+H]⁺).

Example 173 Preparation of[6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of bis-(2-fluoro-phenyl)-methanone

To a stirred suspension of 2-fluorobenzeneboronic acid (280 mg, 2 mmol),Cs₂CO₃ (1.63 g, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (40mg, 0.02 mmol) in toluene (35 ml) under nitrogen was added dropwise2-fluorobenzoyl chloride (634 mg, 4 mmol). The suspension was heated at100° C. for 16 h, cooled to RT and partitioned between ethyl acetate andwater. The organic layer was washed with aqueous potassiumhydrogencarbonate solution, brine, dried over sodium sulfate, filteredand evaporated. Purification by flash chromatography afforded the titlecompound (210 mg, 46%). Colorless liquid.

MS: m/e=218.1 ([M+).

Preparation of bis-(2-fluorophenyl)dichloromethane

The title compound was produced in accordance with the general method ofExample 182a from bis-(2-fluoro-phenyl)-methanone (Example 173a) andused without further purification. Brown solid.

Preparation of[6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-1-yl-methanone (Example 99b)and bis-(2-fluorophenyl)dichloromethane (Example 173b). Light brownamorphous solid.

MS: m/e=442.3 ([M+H]⁺).

Example 174 Preparation of[2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of 2,2′,4,4′-tetrachloro-dichlorodiphenylmethane

The title compound was produced in accordance with the general method ofExample 207a from 2,4-dichlorobenzene and used without furtherpurification. White crystals.

m.p.: 139-142° C.; MS: m/e=373.9, 375.9 ([M]⁺).

Preparation of[2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,2′,4,4′-tetrachloro-dichlorodiphenylmethane and2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 166c).White foam.

MS: m/e=541.9, 543.9 ([M]⁺).

Example 175 Preparation of4-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 108c from 2,2′,4,4′-tetrafluorodiphenyldichloromethane (Example162a) and 4-fluoro-5-(morpholine-1-sulfonyl)-benzene-1,2-diol (Example234b). Off-white foam.

MS: m/e=514.2 ([M+H]⁺).

Example 176 Preparation of4-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 108c from 2,4-dichloro-4′-fluoro-diphenyldichloromethane and4-fluoro-5-(morpholine-1-sulfonyl)-benzene-1,2-diol (Example 234b).Off-white foam.

MS: m/e=528.1 ([M+H]⁺).

Example 177 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 4,4′-difluoropiperidine. Yellow gum.

MS: m/e=526.1 ([M]⁺).

Example 178 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 4-(trifluoromethyl)piperidine hydrochloride.White foam.

MS: m/e=558.0 ([M]⁺).

Example 179 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3S-ethoxy-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 3S-ethoxy-pyrrolidine. Colorless oil.

MS: m/e=520.1 ([M]⁺).

Example 180 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (1R-phenyl-ethyl)-amide

The title compound was produced in accordance with the general method ofExample 108e from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and (1R-phenyl-ethyl)-amine. Colorless oil.

MS: m/e=526.1 ([M]⁺).

Example 181 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(1-oxo-thiomorpholin-4-yl)-methanone

A solution of m-chloroperbenzoic acid (74 mg, 0.3 mmol) indichloromethane (1.2 mL) was added to a cooled (−20° C.) solution of[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone(Example 136) (153 mg, 0.3 mmol) in dichloromethane (1.7 mL). Thereaction mixture was stirred at −20° C. for 3 h, quenched with 5%aqueous sodium thiosulfate solution. The aqueous phase was extractedwith dichloromethane and the combined organic phases were washed with10% sodium bicarbonate solution and brine, dried over sodium sulfate,filtered and the volatiles were removed under vacuo. Purification byflash chromatography afforded the title product as a white foam (141 mg,89%).

MS: m/e=524.1 ([M]⁺).

Example 182 Preparation of[2,2-bis-(2-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of bis-(2-chlorophenyl)dichloromethane

A mixture of 2,2′-dichlorobenzophenone (502 mg, 2 mmol) and phosphoruspentachloride (833 mg, 4 mmol, 2.0 eq.) was stirred 28 h at 170° C. Thereaction mixture was cooled down to room temperature, diluted withdichloromethane and washed with cold water. The organic layer was driedover sodium sulfate, filtered and the volatiles were removed in vacuo,affording the title compound (629 mg, quant.) as an orange oil.

MS: m/e=306.0 ([M]⁺).

Preparation of[2,2-bis-(2-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

A mixture of bis-(2-chlorophenyl)dichloromethane (Example 182, 258 mg,0.84 mmol, 2.6 eq.) and(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 87b,72 mg, 0.32 mmol) were heated 5 h at 150° C. in a sealed glass tube.Purification by flash chromatography afforded the title compound (6.8mg, 4.5%) as an off-white solid, m.p.: 98° C.

MS: m/e=474.0 ([M+H]⁺).

Example 183 Preparation of[6-fluoro-2,2-bis-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of bis-(4-trifluoromethyl-phenyl)-methanone

The title compound was produced in accordance with the general method ofExample 173a from 4-trifluoromethyl-phenylboronic acid and4-trifluoromethyl-benzoyl chloride. White crystalline solid.

MS: m/e=318.1 ([M]⁺).

Preparation of bis-(4-trifluoromethyl-phenyl)dichloromethane

The title compound was produced in accordance with the general method ofExample 87d from bis-(4-trifluoromethyl-phenyl)-methanone (Example 183a)and used without further purification. Brown solid.

Preparation of[6-fluoro-2,2-bis-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-1-yl-methanone (Example 99b)and bis-(4-trifluoromethyl-phenyl)dichloromethane (Example 183b).Light-brown amorphous solid.

MS: m/e=542.1 ([M+H]⁺)

Example 184 Preparation of[6-fluoro-2,2-bis-(3-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of bis-(3-fluorophenyl)dichloromethane

The title compound was produced in accordance with the general method ofExample 87d from bis-(3-fluoro-phenyl)-methanone and used withoutfurther purification. Brown solid.

Preparation of[[6-fluoro-2,2-bis-(3-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-1-yl-methanone (Example 99b)and bis-(3-fluorophenyl)dichloromethane (Example 184a). Off-whiteamorphous solid.

MS: m/e=442.1 ([M+H]⁺).

Example 185 Preparation of[2-(2-chloro-4-fluoro-phenyl)-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from2-chloro-1-[dichloro-(4-fluoro-phenyl)-methyl]-4-fluoro-benzene (Example172a) and (3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 87b).Light brown gum.

MS: m/e=458.3 ([M+H]⁺).

Example 186 Preparation of[2,2-bis-(3,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 1,1′-(dichloromethylene)bis[3,4-difluoro-benzene and(3,4-dihydroxy-phenyl)-piperidin-4-yl-methanone. Light brown gum.

MS: m/e=458.2 ([M+H]⁺).

Example 187 Preparation of[2,2-bis-(3,4-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 1,1′-(dichloromethylene)bis[3,4-difluoro-benzene and(3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 87b). Colorlessgum.

MS: m/e=460.2 ([M+H]⁺).

Example 188 Preparation of[2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone

Preparation of5-bromo-2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c from 2,2′,4,4′-tetrachloro-dichlorodiphenylmethane (Example174a) and 4-bromo-5-fluoro-benzene-1,2-diol (Example 108a). Colorlesssolid.

MS: m/e=507.9, 509.9 ([M]⁺).

Preparation of2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid

The title compound was produced in accordance with the general method ofExample 108d from5-bromo-2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole. Whitefoam.

MS: m/e=471.0, 473.0 ([M−H]⁻)

Preparation of[2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid and 3-pyrrolidinol. Light yellow foam.

MS: m/e=541.9, 543.9 ([M]⁺).

Example 189 Preparation of[2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid and 4-hydroxy-piperidine. Light yellow foam.

MS: m/e=556.0, 558.0 ([M]⁺).

Example 190 Preparation of2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid ethyl-methyl-amide

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid and N-ethylmethylamine. White foam.

MS: m/e=514.0, 516.0 ([M]⁺).

Example 191 Preparation of2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid bis-(2-hydroxy-ethyl)-amide

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-dichloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid and diethanolamine. Light yellow foam.

MS: m/e=560.0, 562.0 ([M]⁺).

Example 192 Preparation of[2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of5-bromo-2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c from dichlorobis(4-chlorophenyl)methane (Example 170a) and4-bromo-5-fluoro-benzene-1,2-diol (Example 108a). Colorless solid.

MS: m/e=437.9, 439.9, 441.9 ([M]⁺).

Preparation of2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylic acid

The title compound was produced in accordance with the general method ofExample 108d from5-bromo-2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxole. Yellowsolid.

MS: m/e=403.1, 405.1 ([M−H]⁻).

Preparation of[2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylic acidand piperidine. White foam.

MS: m/e=472.1, 474.1 ([M]⁺).

Example 193 Preparation of[2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(4-chloro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylic acidand pyrrolidine. White foam.

MS: m/e=458.1, 460.1 ([M]⁺).

Example 194 Preparation of[2,2-bis-(2-chloro-4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of 2,2′-dichloro-4,4′difluorodiphenyldichloromethane

Bis(2-chloro-4-fluorophenyl)-methanone (1.6 g, 5.57 mmol) and phosphoruspentachloride (1.4 g, 6.72 mmol) were heated 5 h at 165° C. in a sealedvial. The mixture was allowed to cool to room temperature, diluted withdichloromethane and poured onto ice. The phases were separated, theorganic phase dried over magnesium sulfate and evaporated to afford thetitle compound as a light brown oil (1.46 g) consisting of a ca. 4:1mixture of desired product and starting ketone (NMR) which was usedwithout further purification.

NMR (300 MHz, CDCl₃) ppm: 8.39 (dd, 2H, J=4.5, 6.6 Hz, product), 7.55(dd, 0.5H, benzophenone), 7.17 (dd, 0.5H, J=4.5, 6.3 Hz, benzophenone),7.10 (m, 4.5H, product and benzophenone), 3.14 (m, 4H), 1.70-1.40 (m,6H).

Preparation of[2,2-bis-(2-chloro-4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,2′-dichloro-4,4′difluorodiphenyldichloromethane and(3,4-dihydroxy-phenyl)-piperidin-4-yl-methanone. Light brown gum.

MS: m/e=490.1 ([M+H]⁺).

Example 195 Preparation of[2,2-bis-(3,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 1,1′-(dichloromethylene)bis[3,4-difluoro-benzene] and(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 99b).Off-white foam.

MS: m/e=478.3 ([M+H]⁺).

Example 196 Preparation of[2,2-bis-(2,5-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of bis-(2,5-difluorophenyl)dichloromethane

The title compound was produced in accordance with the general method ofExample 207a from 2,5-difluorobenzene. Viscous light-brown oil.

MS: m/e=308.1 ([M]⁺).

Preparation of[2,2-bis-(2,5-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-1-yl-methanone (Example 99b)and bis-(2,5-difluorophenyl)dichloromethane (Example 196a). Light brownamorphous solid.

MS: m/e=477.1 ([M]⁺).

Example 197 Preparation of[2,2-bis-(2-chloro-4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,2′-dichloro-4,4′difluorodiphenyldichloromethane(Example 194a) and (3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone(Example 87b). Light yellow gum.

MS: m/e=492.2 ([M+H]⁺).

Example 198 Preparation of[2,2-bis-(2-chloro-4-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,2′-dichloro-4,4′difluorodiphenyldichloromethane(Example 194a) and(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 99b).Off-white foam.

MS: m/e=510.1 ([M+H]⁺).

Example 199 Preparation of[6-chloro-2,2-bis-(2-chloro-4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 2,2′-dichloro-4,4′difluorodiphenyldichloromethane(Example 194a) and(2-chloro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 218b).Light brown foam.

MS: m/e=526.1 ([M+H]⁺).

Example 200 Preparation of2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid amide

The title compound was produced in accordance with the general method ofExample 108e from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and ammonium hydroxide. White foam.

MS: m/e=422 ([M]⁺).

Example 201 Preparation of[2,2-bis-(4-bromo-2-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of 4,4′-dibromo-2,2′-difluoro-benzophenone

Tetrakis(triphenylphosphine)palladium (0.15 g, 0.13 mmol) was dissolvedin anisole (15 mL). 1-Bromo-3-fluoro-4-iodobenzene (2.0 g, 6.6 mmol),4-bromo-2-fluorobenzeneboronic acid (1.45 g, 6.6 mmol) and potassiumcarbonate (2.7 g, 19.9 mmol) together with another 15 mL anisole wereadded. The above mixture was stirred for 16 h at 80° C. under 10 barcarbon monoxide pressure. The reaction mixture was allowed to cool,added to a toluene/water mixture (120 mL, 1:1) the phases were separatedand the water phase was extracted twice with toluene. Organic phaseswere pooled, washed with brine and the solvent was evaporated.Crystallization from hexane afforded the title compound as whitecrystals (1.17 g, 47%).

MS: m/e=375.9, 377.9 ([M+H]⁺).

Preparation of 4,4′-dibromo-2,2′-difluoro-dichlorodiphenylmethane

A mixture of 4,4′-dibromo-2,2′-difluoro-benzophenone (1.3 g, 3.5 mmol),phosphorus oxychloride (26 mL) and phosphorus pentachloride (4.4 g, 21mmol) was stirred at boiling temperature for 72 h. The mixture wascooled and poured into ice/water (200 mL). The product was extractedinto dichloromethane. Organic phases were pooled, dried with sodiumsulfate and the solvent was removed in vacuo yielding the product whichwas used without further purification. Brownish oil.

MS: m/e=429.8, 431.8 ([M]⁺).

Preparation of[2,2-bis-(4-bromo-2-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from 4,4′-dibromo-2,2′-difluoro-dichlorodiphenylmethane and2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 166c).Colorless oil.

MS: m/e=598.0, 600.0,602.0 ([M]⁺).

Example 202 Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3,4-cis-dihydroxy-pyrrolidin-1-yl)-methanone

Preparation of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2,5-dihydro-pyrrol-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid (Example 108d) and 3-pyrroline. Yellow oil.

MS: m/e=474 ([M]⁺).

Preparation of[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3,4-cis-dihydroxy-pyrrolidin-1-yl)-methanone

To a solution of[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(2,5-dihydro-pyrrol-1-yl)-methanone(70 mg, 0.15 mmol) in acetone (3.7 mL) and water (1.5 mL),4-methylmorpholine-4-oxide monohydrate (23 mg, 0.16 mmol), osmiumtetroxide (0.02 mL, 0.0015 mmol) and potassium osmate(VI) dihydrate (2.4mg, 0.0065 mmol) were added and the reaction stirred 24 h at 20° C.Sodium thiosulfate pentahydrate was added, the reaction mixture wasstirred 30 min. and poured onto crushed ice. The aqueous phase wasextracted twice with ethyl acetate and the combined organic phases werewashed with brine, dried over sodium sulfate, filtered and the volatilesremoved in vacuo. Purification by flash chromatography afforded thetitle product as a black oil (56 mg, 74%).

MS: m/e=508.1 ([M]⁺).

Example 203 Preparation of[2,2-bis-(2,3-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of bis-(2,3-difluoro-phenyl)-methanone

The title compound was produced in accordance with the general method ofExample 173a from 2,3-difluorobenzeneboronic acid and2,3-difluoro-benzoyl chloride. Off-white crystalline solid.

MS: m/e=254.1 ([M]⁺).

Preparation of bis-(2,3-difluorophenyl)dichloromethane

The title compound was produced in accordance with the general method ofExample 87d from bis-(2,3-difluoro-phenyl)-methanone (Example 203a) andused without further purification. Brown solid.

Preparation of[2,2-bis-(2,3-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-1-yl-methanone (Example 99b)and bis-(2,3-difluorophenyl)dichloromethane (Example 203b). Off-whiteamorphous solid.

MS: m/e=478.1 ([M+H]⁺).

Example 204 Preparation of[6-fluoro-2,2-bis-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of bis-(4-trifluoromethoxy-phenyl)-methanone

The title compound was produced in accordance with the general method ofExample 173a from 4-trifluoromethoxy-benzeneboronic acid and4-trifluoromethoxy-benzoyl chloride. Light brown solid.

MS: m/e=350 ([M]⁺).

Preparation of bis-(4-trifluoromethoxy-phenyl)dichloromethane

The title compound was produced in accordance with the general method ofExample 182a from bis-(4-trifluoromethoxy-phenyl)-methanone (Example203a) in phosphorus oxychloride and used without further purification.Brown solid.

Preparation of[6-fluoro-2,2-bis-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-1-yl-methanone (Example 99b)and bis-(4-trifluoromethyl-phenyl)dichloromethane (Example 204b).Off-white amorphous solid.

MS: m/e=574.2 ([M+H]⁺).

Example 205 Preparation of[2,2-bis-(2-chloro-4,5-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108c from1,1′-(dichloromethylene)bis[2-chloro-4,5-difluorobenzene and(3,4-dihydroxy-phenyl)-piperidin-4-yl-methanone. Off-white foam.

MS: m/e=526.1 ([M+H]⁺).

Example 206 Preparation of4-[2,2-bis-(2-chloro-4-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 108c from 2,2′-dichloro-4,4′difluorodiphenyldichloromethane(Example 194a) and 4-fluoro-5-(morpholine-1-sulfonyl)-benzene-1,2-diol(Example 234b). Light brown solid.

MS: m/e=546.0 ([M+H]⁺).

Example 207 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of 2,2′,4,4′-tetrafluorodiphenyldichloromethane

To a cooled (10C) mixture of 1,3-difluorobenzene (50 g, 0.438 mol) andaluminium trichloride (33.3 g, 250 mmol, 0.57 eq.) was slowly addedcarbon tetrachloride (91 mL). The reaction mixture was warmed to 30° C.during 4 h. Ice water was added. The aqueous layer was extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and the volatiles were removed in vacuo, affording thetitle compound 60.3 g, 89%) as a dark brown oil.

MS: m/e=273.2 ([M−Cl*]⁺).

Preparation of5-bromo-2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c from 4-bromo-5-fluoro-benzene-1,2-diol (Example 108a) and[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone(Example 207a). Light yellow solid.

MS: m/e=444.0 ([M+H]⁺).

Preparation of2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid

The title compound was produced in accordance with the general method ofExample 108d from5-bromo-2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole(Example 207b). Yellow solid.

MS: m/e=407.0 ([M−H]⁻).

Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and piperidine. Yellow oil.

MS: m/e=476.1 ([M+H]⁺).

Example 208 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-fluoro-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and 4-fluoropiperidine. White solid.

MS: m/e=494.1 ([M+H]⁺).

Example 209 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and 4,4-difluoropiperidine. White solid.

MS: m/e=512.2 ([M+H]⁺).

Example 210 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and 4-(trifluoromethyl)piperidine. Yellow oil.

MS: m/e=544.2 ([M+H]⁺).

Example 211 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and 4-hydroxypiperidine. White solid.

MS: m/e=491.1 ([M+H]⁺).

Example 212 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and 4-hydroxypiperidine. White solid.

MS: m/e=494.1 ([M+H]⁺).

Example 213 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-pyrrolidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and pyrrolidine. White solid.

MS: m/e=462.1 ([M+H]⁺).

Example 214 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(3S-hydroxy-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and 3S-hydroxypyrrolidine. White solid.

MS: m/e=478.1 ([M+H]⁺).

Example 215 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl)-(2S-hydroxymethyl-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole5-carboxylicacid (Example 207c) and L-prolinol. White solid.

MS: m/e=492.2 ([M+H]⁺).

Example 216 Preparation of[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-(2S-methoxymethyl-pyrrolidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-carboxylicacid (Example 207c) and 2S-(methoxymethyl)pyrrolidine. Light yellow oil.

MS: m/e=506.1 ([M+H]⁺).

Example 217 Preparation of(6-chloro-2,2-di-p-tolyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 233d from bis(4-methylphenyl)-methanethione and(2-chloro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 218b).Light brown gum.

MS: m/e450.2 ([M+H]⁺).

Example 218 Preparation of4-[{6-chloro-10′,11′-dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cyclohepten]-5-yl}carbonyl]-morpholine

Preparation of (6-Chloro-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

To a mixture of 6-chloro-1,3-benzodioxole-5-carboxylic acid (0.49 g,2.44mmol) and hydroxybenzotriazole (66 mg, 0.49 mmol) in acetonitrile (20mL) were added morpholine (0.53 mL, 6.1 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.52 g,2.7 mmol). The orange solution was stirred 72 h at room temperature,diluted with ethyl acetate and poured into water. The phases wereseparated and the aqueous phase extracted with ethyl acetate. Thecombined organic phases were washed with brine, dried over magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel to afford the title compound aswhite solid (0.53 g, 80%), mp 155° C.

MS: m/e 270.2 ([M+H]⁺).

Preparation of 2-chloro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone

A 1M solution of boron trichloride in dichloromethane (11 mL) was addeddropwise to a cooled (ice bath) solution of(6-chloro-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone (Example 218a)(1.98 g, 7.34 mmol) in dichloromethane (20 mL). The mixture was stirredovernight at room temperature and diluted with 1M aqueous potassiumdihydrogenphosphate solution (10 mL). After stirring 1 h, the phaseswere separated and the aqueous phase extracted with ethyl acetate. Thecombined organic phases were washed with brine, dried over magnesiumsulfate and evaporated to afford the title compound as brown foam (1.82g, 96%) that was used without further purification.

MS: m/e494.1 ([M+H]⁺).

Preparation of4-[{6-chloro-10′,11′-dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cyclohepten]-5-yl}carbonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 233d from 2,3,6,7-dibenzocycloheptane-1-thione and(2-chloro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 218b).Light brown solid.

MS: m/e 448.1 ([M+H]⁺).

Example 219 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-fluoro-piperidin-1-yl)-methanone

Preparation of6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid

The title compound was produced in accordance with the general method ofExample 108d from5-bromo-6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole (Example164a). Light yellow foam.

MS: m/e=371.2 ([M−H]⁺).

Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-fluoro-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and 4-fluoropiperidine hydrochloride. Yellow oil.

MS: m/e=458.2 ([M+H]⁺).

Example 220 Preparation of(4,4-difluoro-piperidin-1-yl)-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and 4,4′-difluoropiperidine. Yellow oil.

MS: m/e=476.1 ([M+H]⁺).

Example 221 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-trifluoromethyl-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and 4-(trifluoromethyl)piperidine hydrochloride. Yellowoil.

MS: m/e=508.2 ([M+H]⁺).

Example 222 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and thiomorpholine. Off-white foam.

MS: m/e=458.2 ([M+H]⁺).

Example 223 Preparation of(3S-ethoxy-pyrrolidin-1-yl)-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and 3S-ethoxypyrrolidine. Yellow oil.

MS: m/e=470.2 ([M+H]⁺).

Example 224 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-[(S)-(2-methoxymethyl-pyrrolidin-1-yl)]-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and 2S-methoxymethylpyrrolidine. Yellow oil.

MS: m/e=470.2 ([M+H]⁺).

Example 225 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-[(S)-2-hydroxymethyl-pyrrolidin-1-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and L-prolinol. Yellow oil.

MS: m/e=456.1 ([M+H]⁺).

Example 226 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-[(S)-3-hydroxy-pyrrolidin-1-yl]-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and 3S-hydroxypyrrolidine. Yellow foam.

MS: m/e=442.1 ([M+H]⁺).

Example 227 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) 4-hydroxypiperidine. Yellow oil.

MS: m/e=456.1 ([M+H]⁺).

Example 228 Preparation of4-[2,2-bis-(2-chloro-4,5-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 108c from1,1′-(dichloromethylene)bis[2-chloro-4,5-difluorobenzene and4-fluoro-5-(morpholine-1-sulfonyl)-benzene-1,2-diol (Example 234b).Off-white foam.

MS: m/e=582.0 ([M+H]⁺).

Example 229 Preparation of(2,2-di-p-tolyl-benzo[1,3]dioxol-5-yl)-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 233d from bis(4-methylphenyl)-methanethione and(3,4-dihydroxy-phenyl)-piperidin-4-yl-methanone. Off-white foam.

MS: m/e 414.2 ([M+H]⁺).

Example 230 Preparation of(2,2-di-p-tolyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 233d from bis(4-methylphenyl)-methanethione and(3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 87b). Off-whitefoam.

MS: m/e 416.2 ([M+H]⁺).

Example 231 Preparation of4-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and morpholine. Yellow gum.

MS: m/e=478.1 ([M+H]⁺).

Example 232 Preparation of4-(6-fluoro-2,2-di-p-tolyl-benzo[1,3]dioxole-5-sulfonyl)-morpholine

The title compound was produced in accordance with the general method ofExample 233d from bis(4-methylphenyl)-methanethione and4-fluoro-5-(morpholine-1-sulfonyl)-benzene-1,2-diol (Example 234b).Light brown gum.

MS: m/e 470.1 ([M+H]⁺).

Example 233 Preparation of1-{6-fluoro-10′,11′-dihydrospiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}sulfonyl]-piperidine

Preparation of 2-fluoro-4,5-dimethoxy-benzenesulfonyl chloride

To a suspension of sulfur trioxide N,N-dimethylformamide complex (4.108g, 27 mmol) in 1,2-dichloroethane was added 4-fluoroveratrole (3.49 g,22 mmol) dropwise. The mixture was slowly heated to 85° C. in an oilbath. After 2.5 h, the solids had dissolved to afford a golden yellowsolution. A trace of starting material was still present and heating wascontinued for a further 4.5 h. The oil bath was removed and thionylchloride (1.95 mL, 27 mmol) added dropwise. The mixture was heated 4 hat 85° C. and allowed to cool to room temperature. The solution waspoured into water and extracted with dichloromethane (3×50 mL), thecombined organics washed with water, dried over magnesium sulfate andevaporated. Remaining traces of N,N-dimethylformamide were removedazeotropically with toluene to afford the product as an off-white solidthat was used without further purification.

MS: m/e 254.0 ([M]⁺).

Preparation of 1-(2-fluoro-4,5-dimethoxy-benzenesulfonyl)-piperidine

Piperidine (4.15 ml, 42.02 mmol) was slowly added to a cooled (ice-bath)solution of 2-fluoro-4,5-dimethoxy-benzenesulfonyl chloride (5 g, 19.63mmol) in dichloromethane (110 mL). The mixture was stirred overnight atroom temperature, diluted with dichloromethane and poured into water.The aqueous phase was extracted with dichloromethane and the combinedorganic phases washed with brine, dried over magnesium sulfate andevaporated. The crude product was used without further purification.

NMR (300 MHz, CDCl₃) ppm: 7.23 (d, 1H, J=6 Hz), 6.71 (d, 1H, J=11 Hz),3.93 (s, 3H), 3.90 (s, 3H), 3.14 (m, 4H), 1.70-1.40 (m, 6H).

Preparation of 4-fluoro-5-(piperidine-1-sulfonyl)-benzene-1,2-diol

A 1M solution of boron tribromide in dichloromethane (58 mL) was addeddropwise to a cooled solution of1-(2-fluoro-4,5-dimethoxy-benzenesulfonyl)-piperidine (5.89 g, 19.42mmol) in dichloromethane (100 mL), maintaining the temperature between10 and 20° C. The mixture was stirred overnight at room temperature andpoured into 1M aqueous potassium dihydrogenphosphate and ice. Afterstirring 1 h, the phases were separated and the aqueous phase extractedwith ethyl acetate. The combined organic phases were washed with brine,dried over magnesium sulfate and evaporated. The residue was purified bycolumn chromatography on silica gel (10:1 dichloromethane/methanoleluant) to afford the title compound as a brown gum (4.17 g, 78%)

MS: m/e 274.1 ([M−H]⁺).

Preparation of1-{6-fluoro-10′,11′-dihydrospiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}sulfonyl]-piperidine

A mixture of 2,3,6,7-dibenzocycloheptane-1-thione (0.281 g, 1.25 mmol),4-fluoro-5-(piperidine-1-sulfonyl)-benzene-1,2-diol (0.230 g, 0.84mmol), copper (I) chloride (0.207 g, 2.09 mmol) and triethylamine (0.46mL, 3.34 mmol) were heated in acetonitrile (5 mL) 4 h at reflux. Themixture was allowed to cool to room temperature and filtered through asmall pad of silica gel, eluting with 1:1 ethyl acetate/heptane. Thesolvent was evaporated under reduced pressure and the residue purifiedby column chromatography on silica gel (15:1 heptane/ethyl acetateeluant) to afford the product as a light yellow foam (0.215 g,55%)

MS: m/e 465.2 ([M]⁺).

Example 234 Preparation of4-{6-fluoro-10′,11′-dihydrospiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}sulfonyl]-morpholine

Preparation of 1-(2-fluoro-4,5-dimethoxy-benzenesulfonyl)-piperidine

The title compound was produced in accordance with the general method ofExample 233c) from 2-fluoro-4,5-dimethoxy-benzenesulfonyl chloride(Example 233a) and morpholine. Colorless solid, mp 107-108° C.

MS: m/e 305.1 ([M]⁺).

Preparation of 4-fluoro-5-(morpholine-1-sulfonyl)-benzene-1,2-diol

The title compound was produced in accordance with the general method ofExample 233c from 1-(2-fluoro-4,5-dimethoxy-benzenesulfonyl)-piperidine(Example 234a). Light brown solid.

MS: m/e 276.0 ([M−H]⁺).

Preparation of4-{6-fluoro-10′,11′-dihydrospiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}sulfonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 233d from 2,3,6,7-dibenzocycloheptane-1-thione and4-fluoro-5-(morpholine-1-sulfonyl)-benzene-1,2-diol (Example 234b).Light yellow solid.

MS: m/e 467.2 ([M]⁺).

Example 235 Preparation of4-[{10′,11′-dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}carbonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 233d from 2,3,6,7-dibenzocycloheptane-1-thione and(3,4-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 87b). Lightyellow gum.

MS: m/e 414.2 ([M+H]⁺).

Example 236 Preparation of1-[{10′,11′-dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cycloheptene]-5-yl}carbonyl]-piperidine

The title compound was produced in accordance with the general method ofExample 233d from 2,3,6,7-dibenzocycloheptane-1-thione and(3,4-dihydroxy-phenyl)-piperidin-4-yl-methanone. Light yellow gum.

MS: m/e 412.2 ([M+H]⁺).

Example 237 Preparation of[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(3-methoxy-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(Example 219a) and 3-methoxypiperidine. Colorless oil.

MS: m/e=470.1 ([M+H]⁺).

Example 240 Preparation of1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and pyrrolidine. Off white solid.

MS: m/e=462.1 ([M+H⁺)].

Example 241 Preparation of1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and piperidine. Yellow solid.

MS: m/e=476.1 ([M+H⁺)].

Example 242 Preparation of4-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-thiomorpholine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and thiomorpholine. Off white solid.

MS: m/e=494.1 ([M+H⁺)].

Example 243 Preparation of1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-piperidine

The title compound was produced in accordance with the general method ofExample 108c from 2,2′,4,4′-tetrafluorodiphenyldichloromethane (Example162a) and 4-fluoro-5-(piperidine-1-sulfonyl)-benzene-1,2-diol (Example233c). Light yellow gum.

MS: m/e=512.3 ([M+H]⁺)

Example 244 Preparation of1-[2,2-bis-(2-chloro-4-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-piperidine

The title compound was produced in accordance with the general method ofExample 108c from 2,2′-dichloro-4,4′difluorodiphenyldichloromethane(Example 194a) and 4-fluoro-5-(piperidine-1-sulfonyl)-benzene-1,2-diol(Example 233c). Colorless gum.

MS: m/e=544.1 ([M+H]⁺).

Example 245 Preparation of the1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidine

Preparation of5-bromo-2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c d from 2,2′,4,4′-tetrafluorodiphenyldichloromethane(Example 207 a) and 4-bromo-5-fluoro-benzene-1,2-diol (Example 108a).Light yellow oil.

MS: m/e=444.0 ([M+H]⁺).

Preparation of2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5 sulfinic acid

To a cooled (-78° C.) solution of5-bromo-2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole (7.3 g,16 mmol) in diethylether (48 mL) was added a solution of n-butyl lithiumin hexanes (1.6 M, 10.3 mL, 16 mmol, 1.0 eq.). After 1 h at −78° C.,sulfur dioxide was bubbled into the solution for 45 min. The reactionmixture was flushed with nitrogen and the reaction mixture was allowedto warm to 0° C. The reaction was neutralized with aqueous hydrochloricacid (0.5N), diluted with dichloromethane and the organic layer waswashed with water, dried over sodium sulfate and the volatiles wereremoved in vacuo. Purification by flash chromatography afforded thetitle compound (4.2 g, 60%) as a white solid.

MS: m/e=427.0 ([M−H]⁻).

Preparation of2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride

To a solution of2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5 sulfinic acid(3.2 g, 7 mmol) in chloroform (25 mL) was added N-chlorosuccinimide (1.0g, 7 mmol, 1.0 eq.) at 20° C. After 40 min, the reaction mixture wasfiltered and the filtrate was evaporated. The residue was suspended indichloromethane, dried over sodium sulfate and the solvent was removedin vacuo, affording the title product as a light yellow gum.

MS: m/e=462.0 ([M+H]⁺).

Preparation of1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidine

To a solution of2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (250 mg, 0.54 mmol) in diethylether (3 mL) was addedpyrrolidine (0.11 mL, 1.35 mmol, 2.5 eq.). The reaction mixture wasdiluted with ethyl acetate (50 mL), washed with an aqueous solution ofhydrochloric acid (IN), brine and water. The organic layer was driedover sodium sulfate and the volatiles were removed in vacuo.Purification by flash chromatography afforded the title compound (198mg, 74%) as a white foam.

MS: m/e=498.2 ([M+H]⁺).

Example 246 Preparation of1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-4-fluoro-piperidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and 4-fluoropiperidine. White foam.

MS: m/e=530.1 ([M+H]⁺).

Example 247 Preparation of1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-4,4-difluoro-piperidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and 4,4-difluoropiperidine. White foam.

MS: m/e=548.1 ([M+H]⁺).

Example 248 Preparation of1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-4-trifluoromethyl-piperidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and 4-trifluoromethylpiperidine hydrochloride.White foam.

MS: m/e=580.2 ([M+H]⁺).

Example 249 Preparation of4-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-thiomorpholine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and thiomorpholine. White foam.

MS: m/e=530.0 ([M+H]⁺).

Example 250 Preparation of1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-2S-methoxymethyl-pyrrolidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and (2S)-methoxymethylpyrrolidine. White foam.

MS: m/e=542.2 ([M+H]⁺).

Example 251 Preparation of2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonic acid(2S-methoxymethyl-pyrrolidin-1-yl)-amide

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and 1-amino-(2S)-methoxymethylpyrrolidine.Yellow viscous oil.

MS: m/e=556.1 ([M−H)⁻].

Example 252 Preparation of{1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidin-2S-yl}-methanol

The title compound was produced in accordance with the general method ofExample 245d from2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and L-prolinol. White foam.

MS: m/e=528.2 ([M−H⁻)].

Example 253 Preparation of1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidin-3S-ol

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and 3S-hydroxypyrrolidine. White foam.

MS: m/e=514.2 ([M−H⁻)].

Example 254 Preparation of1-[2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-piperidin-4-ol

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 245c) and 4-hydroxypiperidine. White foam.

MS: m/e=528.2 ([M−H)⁻].

Example 255 Preparation of1-[2,2-bis-(2-chloro-4,5-difluoro-phenyl)6-fluoro-benzo[1,3]dioxol-5-sulfonyl]-piperidine

The title compound was produced in accordance with the general method ofExample 108c from1,1′-(dichloromethylene)bis[2-chloro-4,5-difluorobenzene and4-fluoro-5-(piperidine-1-sulfonyl)-benzene-1,2-diol (Example 233c).Off-white foam.

MS: m/e=580.1 ([M+H]⁺).

Example 256 Preparation of4-[{6-fluoro-10′,11′-dihydro-spiro[1,3-benzodioxole-2,5′-[5H]dibenzo[a,d]cyclohepten]-5-yl}-carbonyl]-morpholine

The title compound was produced in accordance with the general method ofExample 233d from 2,3,6,7-dibenzocycloheptane-1-thione and(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 99b).Light brown solid.

MS: m/e 432.3 ([M+H]⁺).

Example 257 Preparation of(6-fluoro-2,2-di-p-tolyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone

The title compound was produced in accordance with the general method ofExample 233d from bis(4-methylphenyl)-methanethione and(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone (Example 99b).Light brown gum.

MS: m/e 434.3 ([M+H]⁺).

Example 258 Preparation of1-(6-fluoro-2,2-di-p-tolyl-benzo[1,3]dioxole-5-sulfonyl)-piperidine

The title compound was produced in accordance with the general method ofExample 233d from bis(4-methylphenyl)-methanethione and4-fluoro-5-(piperidine-1-sulfonyl)-benzene-1,2-diol (Example 233c).Light yellow gum.

MS: m/e 470.2 ([M+H]⁺).

Example 259 Preparation of[6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-ylmethanone

Preparation of5-bromo-6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole

The title compound was produced in accordance with the general method ofExample 108c from 4-bromo-5-fluoro-benzene-1,2-diol (Example 108a) andbis-(2-fluoro-phenyl)methanone (Example 173a). Colorless solid.

MS: m/e=407.9 ([M]⁺).

Preparation of6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid

The title compound was produced in accordance with the general method ofExample 108d from5-bromo-6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole and carbondioxide. Light brown solid.

MS: m/e=371.2 ([M−H]⁺).

Preparation of[6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acidand piperidine, with(benzotriazol-1-yl-oxy-tris-dimethylamino)-phosphoniumhexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature (reactiontime 20 h). Off-white solid.

MS: m/e=440.3 ([M+H]⁺).

Example 260 Preparation of[6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(4-hydroxy-piperidin-1-yl)-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acidand 4-hydroxy-piperidine, with(benzotriazol-1-yl-oxy-tris-dimethylamino)-phosphoniumhexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature (reactiontime 20 h). Off-white solid.

MS: m/e=456.2 ([M+H]⁺).

Example 261 Preparation of4-fluoro-1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

Preparation of6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfinic acid

The title compound was produced in accordance with the general method ofExample 245b from5-bromo-6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole (Example164a). Off-white foam.

MS: m/e=391.1 ([M−H]⁻).

Preparation of6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl chloride

The title compound was produced in accordance with the general method ofExample 245c from6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfinic acid(Example 261a). Yellow oil.

MS: m/e=426.0 ([M+H]⁺).

Preparation of4-fluoro-1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and 4-fluoropiperidine. White foam.

MS: m/e=494.4 ([M+H]⁺).

Example 262 Preparation of4,4-difluoro-1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and 4,4-difluoropiperidine. White foam.

MS: m/e=512.4 ([M+H]⁺).

Example 263 Preparation of1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-4-trifluoromethyl-piperidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and 4-(trifluoromethyl)-piperidinehydrochloride. White foam.

MS: m/e=544.4 ([M+H]⁺).

Example 264 Preparation of1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-2S-methoxymethyl-pyrrolidine

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and 2S-methoxymethylpyrrolidine. White foam.

MS: m/e=506.3 ([M+H]⁺).

Example 265 Preparation of1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-pyrrolidin-3S-ol

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and 3S-hydroxypyrrolidine. White foam.

MS: m/e=478.2 ([M+H]⁺).

Example 266 Preparation of1-[6-fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-piperidin-4-ol

The title compound was produced in accordance with the general method ofExample 245d from2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonylchloride (Example 261b) and 4-hydroxypyrrolidine. White solid.

MS: m/e=491.1 ([M+H]⁺).

Example 267 Preparation of[2,2-bis-(3-chloro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of bis-(3-chloro-phenyl)-methanol

This compound was prepared from 3-chloro-iodobenzene according toExample 269a; light yellow oil,

MS: m/e=252 ([M]⁺).

Preparation of bis-(3-chloro-phenyl)-methanone

This compound was prepared from bis-(3-chloro-phenyl)-methanol accordingto Example 269b; white solid, m.p.: 117° C.,

MS: m/e=250 ([M]⁺).

Preparation of bis-(3-chloro-phenyl)-dichloromethane

This compound was prepared from bis-(3-chloro-phenyl)-methanone and PCl₅according to Example 269c;

MS: m/e=306 ([M⁺)].

Preparation of 2,2-bis-(3-chloro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid ethyl ester

This compound was prepared from bis-(3-chloro-phenyl)-dichloromethaneand ethyl 3,4-dihydroxybenzoate according to Example 269d; yellowviscous oil, MS: m/e=415 ([M+H]⁺).

Preparation of 2,2-bis-(3-chloro-phenyl)-benzo[1,3]dioxole-5-carboxylicacid

This compound was prepared from2,2-bis-(3-chloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid ethylester according to Example 269e; white solid, m.p.: 166° C., MS: m/e=386([M−H]⁻).

Preparation of[2,2-bis-(3-chloro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

This compound was prepared from2,2-bis-(3-chloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid andpiperidine according to Example 269f; light yellow solid, mp.: 54° C.,

MS: m/e=454 ([M+H]⁺).

Example 268 Preparation of[2,2-bis-(4-cyano-2-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

A mixture of[2,2-bis-(4-bromo-2-fluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]morpholin-4-yl-methanone (0.3 g, 0.5 mmol), copper (I) cyanide (0.81g), tris(dibenzylideneacetone)dipalladium(0) chloroform complex (78 mg),tetraethylammonium cyanide (226 mg) and1,1′-bis-(diphenylphosphino)-ferrocene (165 mg) was boiled for 3 days indioxane (8 mL). Ethyl acetate (60 mL) and sodium bicarbonate (60 mL)were added to the cooled mixture, the phases were separated and theaqueous phase extracted with ethyl acetate. Organic phases were pooled,washed with brine and dried with sodium sulfate. Volatiles were removedand the residue was purified by chromatography on silica gel (ethylacetate/heptane) to afford the title product as a light yellow foam(0.17 g; 71%).

MS: m/e=491.1 ([M]⁺).

Example 269 Preparation of[2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of bis-(3,5-difluoro-phenyl)-methanol

A mixture of 486 mg magnesium, 8 mL dry ether, a small amount of3,5-difluoro-bromobenzene and some iodine was warmed to start theGrignard reaction. 2.38 mL 3,5-difluoro-bromobenzene in 40 mL dry etherwere added dropwise and the mixture refluxed for one hour. 0.81 mL ethylformate was added and the mixture stirred for 21 hours at roomtemperature. The reaction was quenched with 7 mL 1N hydrochloric acid,diluted with ethyl acetate and washed with water and brine. Evaporationof the solvents and chromatography of the residue afforded 1.56 g of alight yellow solid, m.p.: 62° C.; MS: 315 ([M+AcO]⁻).

Preparation of bis-(3,5-difluoro-phenyl)-methanone

1.56 g bis-(3,5-difluoro-phenyl)-methanol, 1.06 g MnO2 and 36 mL1,2-dichloroethane were refluxed for 4 hours. The mixture was cooled,filtered and evaporated. Chromatography of the residue afforded 1.47 gof a white solid, m.p.: 79° C.; MS: 254 ([M]⁺).

Preparation of bis-(3,5-difluoro-phenyl)-dichloromethane

508 mg bis-(3,5-difluoro-phenyl)-methanone and 833 mg PCl₅ were placedin a sealed glass tube and heated to 170° C. for 7 hours. The reactionmixture was diluted with dichloromethane and washed twice with water andice. Evaporation of the solvent afforded 333 mg of light yellow oil,which was not further purified.

Preparation of2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid ethylester

239 mg dichloro-bis(3,5-difluorophenyl)methane and 141 mg ethyl3,4-dihydroxybenzoate were heated to 180° C. for 2 h 15 min. The brownmixture was diluted with dichloromethane, washed with sat. NaHCO₃solution and water. The dried solution was evaporated and the residuepurified on silica gel to provide 284 mg resinous oil. MS: 419 ([M+H]⁺).

Preparation of2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid

267 mg 2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acidethyl ester, 3.8 mL ethyl alcohol and 0.96 mL 1N NaOH were stirred atroom temperature for 6 h. The solvent was evaporated and the residueworked up with ethyl acetate, diluted hydrochloric acid and water.Purification on silica gel afforded 204 mg white crystals, m.p.: 96° C.;MS: 389 ([M−H]⁻).

Preparation of[2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

96 mg 2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid,93 mg HBTU, 1 mL DMF and 50 mg N-methylmorpholine were stirred at roomtemperature. After 5 min 21 mg piperidine were added and the mixturestirred at room temperature for 24 h. The mixture was diluted with ethylacetate and washed twice with water. Evaporation of the solvents andpurification on silica gel afforded 111 mg of a white foam, MS: 457([M]⁺).

Example 270 Preparation of[2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

This compound was prepared from2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid andmorpholine according to Example 269f; white foam, MS 459 ([M]⁺).

Example 271 Preparation of6-fluoro-[2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-[(S)-3-hydroxy-pyrrolidin-1-yl)]-methanone

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acidand (S)-3-hydroxy-pyrrolidine, with(benzotriazol-1-yl-oxy-tris-dimethylamino)-phosphoniumhexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature).

MS: m/e=442.3 ([M+H]⁺).

Example 272 Preparation of6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acidethyl-methyl-amide

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acidand ethyl-methyl-amine, with(benzotriazol-1-yl-oxy-tris-dimethylamino)-phosphoniumhexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature.

MS: m/e=414.3 ([M+H]⁺).

Example 273 Preparation of6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid(2-methoxy-ethyl)-methyl-amide

The title compound was produced in accordance with the general method ofExample 108e from6-fluoro-2,2-bis-(2-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acidand (2-methoxy-ethyl)-methyl-amine, with(benzotriazol-1-yl-oxy-tris-dimethylamino)-phosphoniumhexafluorophosphate (BOP) as coupling reagent (instead of carbonyldiimidazole) in acetonitrile as solvent at room temperature.

MS: m/e=444.3 ([M+H]⁺).

Example 274 Preparation of[2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of bis-(3,5-dichloro-phenyl)-methanol

This compound was prepared from 3,5-dichloro-iodobenzene according toExample 269a; off white solid, m.p.: 126° C.; MS: m/e=322 ([M]⁺).

Preparation of bis-(3,5-dichloro-phenyl)-methanone

This compound was prepared from bis-(3,5-dichloro-phenyl)-methanolaccording to Example 269b; off white solid, m.p.: 157° C.; MS: m/e=320([M]⁺).

Preparation of bis-(3,5-dichlorophenyl)dichloromethane

This compound was prepared from bis-(3,5-dichloro-phenyl)-methanone andPC₅ according to Example 269c; light red solid.

Preparation of2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid ethylester

This compound was prepared from bis-(3,5-dichlorophenyl)dichloromethaneand ethyl 3,4-dihydroxybenzoate according to Example 269d; light redsolid, m.p.: 89° C.; MS: m/e=484 ([M]⁺).

Preparation of2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid

This compound was prepared from2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid ethylester according to Example 269e; white foam,

MS: m/e=455 ([M−H]⁻).

Preparation of[2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

This compound was prepared from2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid andpiperidine according to Example 269f; waxy solid,

MS: m/e=([M+H]⁺).

Example 275 Preparation of[2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

This compound was prepared from2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid andmorpholine according to Example 269f; waxy solid,

MS: m/e=526 ([M+H]⁺).

Example 276 Preparation of[2,2-bis-(3-bromo-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of bis-(3-bromophenyl)-dichloromethane

340 mg bis-(3-bromo-phenyl)-methanone, 0.08 mL DMF and 5 mLthionylchloride were refluxed for 24 hours. The solvents were evaporatedin vacuo to give an off white waxy solid,

MS: m/e=394 ([M]⁺).

Preparation of[2,2-bis-(3-bromo-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

79 mg bis-(3-bromophenyl)-dichloromethane and 48 mg(2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone were heated to180° C. for one hour. Chromatography of the dark residue gave 30 mg ofan off-white waxy solid, MS: m/e=564 ([M+H])⁺.

Example 277 Preparation of[6-fluoro-2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

Preparation of dichloro-bis-(3-methoxyphenyl)-methane

This compound was prepared according to Example 276a; brown liquid.

Preparation of[6-fluoro-2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

This compound was prepared according to Example 276b; light brown, waxysolid,

MS: m/e=466 ([M+H]⁺).

Example 278 Preparation of[2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

Preparation of 2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxole-5-carboxylicacid ethyl ester

This compound was prepared from dichloro-bis-(3-methoxyphenyl)-methaneand ethyl 3,4-dihydroxybenzoate according to Example 269d; the crudeproduct was used for the next step.

Preparation of 2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxole-5-carboxylicacid

This compound was prepared from2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxole-5-carboxylic acid ethylester according to Example 269e; waxy solid,

MS: m/e=377 ([M−H]⁻).

Preparation of[2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-piperidin-1-yl-methanone

This compound was prepared from2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxole-5-carboxylic acid andpiperidine according to Example 269f; waxy solid, MS: m/e=446 ([M+H]⁺].

Example 279 Preparation of[2,2-bis-(3-chloro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone

This compound was prepared from bis-(3-chloro-phenyl)-dichloromethaneand (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone accordingto Example 276b; viscous brown oil, MS: m/e=474 ([M+H]⁺).

Galenical Examples Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mgMicrocrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg FilmCoat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxyde (yellow) 0.8 mg 1.6 mgTitan dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcristallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidon in water. The granulate is mixed with sodium starchglycolate and magesiumstearate and compressed to yield kernels of 120 or350 mg respectively. The kernels are lacquered with an aq.solution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mgMaize starch 20.0 mg Talc 5.0 mgThe components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg AceticAcid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by AceticAcid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

1. A compound of the formula:

or a pharmaceuticall acceptable salt thereof, wherein: R¹ and R² areindependently unsubstituted phenyl, or phenyl which is mono-, di- ortri-substituted, independently, by hydroxy, lower alkyl, lower alkoxy,perfluoro-lower alkyl, perfluoro-lower alkoxy, alkanoyl, cyano, nitro orhalogen; or R¹ and R² together with the carbon atom to which they areattached form a 10′,11′-dihydro-2,5′-[5H]dibenzo-[a,d]cyclohepteneresidue; R³ and R⁴ are independently hydrogen, halogen, hydroxy, loweralkyl, lower alkoxy, perfluoro-lower alkyl, alkanoyl or cyano; R⁵ and R⁶together with the nitrogen atom to which they are attached form aheterocyclic ring which is peperazinyl, azepanyl, diazepanyl, orthiomorpholino, which is optionally mono-, di- or tri-substituted,independently, by lower alkyl, lower alkoxycarbonyl, hydroxy loweralkyl, lower alkoxy-lower alkyl, di-lower alkylcarbamoyl, carbamoyl,lower alkylcarbonyl amino, oxo, dioxo, alkanoyl, amino lower alkyl,hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano, pyridinylor pyrazinyl, or by phenyl or phenyl lower alkyl, wherein the phenylmoiety may optionally be mono-, di- or tri-substituted, independently,by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy,alkanoyl or cyano; R⁷ is hydrogen, halogen, lower alkyl or cyano; and Xis a single bond, —CH₂—, —C(O)—, —SO₂— or —SO₂NH—.
 2. The compound ofclaim 1, wherein R¹ and R² are independently phenyl, optionally mono-,di- or tri-substituted, independently, by hydroxy, lower alkyl, loweralkoxy, perfluoro-lower alkyl, alkanoyl, cyano or halogen; R³ and R⁴ areindependently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy,perfluoro-lower alkyl, alkanoyl or cyano; R⁵ and R⁶ together with thenitrogen atom to which they are attached form a heterocyclic ring whichis piperazinyl, azepanyl, diazepanyl, or thiomorpholino, which isoptionally mono-, di- or tri-substituted, independently, by lower alkyl,lower alkoxycarbonyl, hydroxy lower alkyl, alkanoyl, amino lower alkyl,hydroxy, lower alkoxy, halogen, perfluoro-lower alkyl, cyano,pyridinylor pyrazinyl, or by phenyl or phenyl lower alkyl, wherein the phenylmoiety may optionally be mono-, di- or tri-substituted, independently,by lower alkyl, lower alkoxy, halogen, perfluoro-lower alkyl, hydroxy,alkanoyl or cyano; R⁷ is hydrogen; and X is —CH₂—, —C(O)— or —SO₂—or apharmaceutically acceptable salt thereof.
 3. The compound of claim 1,wherein R¹ and R² are independently unsubstituted phenyl or phenyl whichis mono-, di- or tri-substituted, independently, by lower alkyl, loweralkoxy, perfluoro-lower alkyl, perfluoro-lower alkoxy, cyano, nitro orhalogen.
 4. The compound of claim 1, wherein R¹ and R² are independentlyphenyl which is mono- or di-substituted, independently, by halogen or bylower alkoxy.
 5. The compound of claim 1, wherein R¹ and R² togetherwith the carbon atom to which they are attached form a10′,11′-dihydro-2,5′-[5H]dibenzo[a,d]cycloheptene residue.
 6. Thecompound of claim 1, wherein R³ and R⁴ are independently hydrogen,hydroxy or halogen.
 7. The compound of claim 1, wherein R³ and R⁴ arehydrogen.
 8. The compound of claim 1, wherein R⁵ and R⁶ together withthe nitrogen atom to which they are attached form a heterocyclic ringwhich is piperazinyl, azepanyl, diazepanyl, or thiomorpholino, which isoptionally mono-, di- or tri-substituted, independently, by lower alkyl,lower alkoxycarbonyl, hydroxy lower alkyl, lower alkoxy-lower alkyl,di-lower alkylcarbamoyl, carbamoyl, lower alkylcarbonyl amino, oxo,alkanoyl, amino lower alkyl, hydroxy, lower alkoxy, halogen,perfluoro-lower alkyl, cyano, pyridinyl or pyrazinyl,or by phenyl orphenyl lower alkyl, wherein the phenyl moiety may optionally be mono-,di- or tri-substituted, independently, by lower alkyl, lower alkoxy,halogen, perfluoro-lower alkyl, hydroxy, alkanoyl or cyano.
 9. Thecompound of claim 8, wherein R⁵ and R⁶ together with the nitrogen atomto which they are attached are piperazinyl, thiomorpholino, azepanyl, ordiazepanyl, which is optionally mono-, di- or tri-substituted,independently, by lower alkyl, lower alkoxycarbonyl, hydroxy loweralkyl, lower alkoxy-lower alkyl, di-lower alkylcarbamoyl, carbamoyl,lower alkylcarbonyl amino, oxo, dioxo, alkanoyl, hydroxyl, lower alkoxy,halogen, perfluoro-lower alkyl,pyridinyl or pyrazinyl, or by phenyl orphenyl lower alkyl, wherein the phenyl moiety may optionally be mono-,di- or tri-substituted, independently, by lower alkyl, lower alkoxy,halogen, or perfluoro-lower alkyl.
 10. The compound of claim 9, whereinR⁵ and R⁶ together with the nitrogen atom to which they are attached ispiperazinyl optionally mono- or di-substituted, independently, byhydroxy or by halogen.
 11. The compound of claim 1, wherein R⁷ ishydrogen.
 12. The compound of claim 1, wherein R⁷ is cyano, halogen orlower alkyl.
 13. The compound of claim 1, wherein X is —C(O)—or—SO₂—.14. A compound selected from the group consisting of:1-(4-Chloro-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine,1-(2,3-Dimethyl-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine,1-(2,4-Dichloro-phenyl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-fluoro-phenyl)-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(3-chloro-phenyl)-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-phenyl-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(3-methoxy-phenyl)-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-methoxy-phenyl)-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-methoxy-phenyl)-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-chloro-phenyl)-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(2-fluoro-phenyl)-piperazine,1-Benzo[1,3]dioxol-5-yl-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-piperazine,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-methyl-[1,4]diazepane,1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-4-(2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl)-[1,4]diazepane,1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-methyl-piperazine,4-(2,2-Diphenyl-benzo[1,3]dioxole-5 -carbonyl)-piperazine-1-carbaldehyde, (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone,(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-isopropyl-piperazin-1-yl)-methanone,[4-(5-Chloro-2-methoxy-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone, ( 2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-m-toly1-piperazin-1-yl) -methanone,(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-o-toly1-piperazin-1-yl)-methanone,[4-(2,3-Dichioro-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone,[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-(2,2-diphenyl-benzo[1,3]dioxol-5-yl)-methanone, (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-methanone,(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone,(4-Fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone,(4,7-Dichloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone,(7-Bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-(4-methyl-piperazin-1-yl)-methanone, andpharmaceutically acceptable salts thereof.
 15. A compound selected fromthe group consisting of: (6-Fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone,[6-Fluoro-2-(4-fluoro-phenyl)-2-phenyl-benzo[1,3]dioxol-5-yl]-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone,[2-(2-Chloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone,[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-5-yl]-[4-(4-fluoro-phenyl)-piperazin-1 -yl]-methanone,2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid azepan-1-ylamide,Azepan-1-yl-[2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-methanone,[2-(2,4-Dichioro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone,[2-(2,4-Dichioro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone,[2-(2,4-Dichioro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-(1-oxo-thiomorpholin-4-yl)-methanone,[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone,[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone,4-[6-Fluoro-2,2-bis-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-sulfonyl]-thiomorpholine,4-[2,2-Bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5-sulfonyl]-thiomorpholine,and pharmaceutically acceptable salts thereof.
 16. A compound which is[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-thiomorpholin-4-yl-methanone,or a pharmaceutically acceptable salt thereof.